Phenylalanine enamide derivatives

ABSTRACT

Phenylalanine enamide derivatives of formula (1) are described:  
                 
wherein 
         R 1  is a group Ar 1 L 2 Ar 2 Alk- in which:    Ar 1  is an optionally substituted aromatic or heteroaromatic group;    L 2  is a covalent bond or a linker atom or group;    Ar 2  is an optionally substituted arylene or heteroarylene group; 
 
and Alk is a chain  
                 
   in which R is a carboxylic acid (—CO 2 H) or a derivative or biostere thereof;    X is an —O— or —S— atom or —N(R 2 )— group in which:    R x , R y  and R z  which may be the same or different is each a hydrogen atom or an optional substituent;    or R z  is an atom or group as previously defined and R x  and R y  are joined together to form an optionally substituted spiro linked cycloaliphatic or heterocycloaliphatic group; and the salts, solvates, hydrates and N-oxides thereof. The compounds are able to inhibit the binding of integrins to their ligands and are of use in the prophylaxis and treatment of immuno or inflammatory disorders or disorders involving the inappropriate growth or migration of cells.

REFERENCE TO RELATED APPLICATIONS

The present application claims priority of Patent Application No. GBRI0104418.9, filed Feb. 22, 2001, Patent Application No. GBRI 0114000.3,filed Jun. 8, 2001 and Patent Application No. GBRI 0127562.7, filed Nov.16, 2001, which are incorporated by reference herein in their entirety.

FIELD OF INVENTION

This invention relates to a series of phenylalanine enamide derivatives,to compositions containing them, to processes for their preparation, andto their use in medicine.

Each of the patents, publications, and other documents mentioned orreferred to in this specification be herein incorporated by reference intheir entirety.

Over the last few years it has become increasingly clear that thephysical interaction of inflammatory leukocytes with each other andother cells of the body plays an important role in regulating immune andinflammatory responses [Springer, T. A., Nature, 346, 425, (1990);Springer, T. A., Cell, 76, 301, (1994)]. Specific cell surface moleculescollectively referred to as cell adhesion molecules mediate many ofthese interactions.

The adhesion molecules have been sub-divided into different groups onthe basis of their structure. One family of adhesion molecules which isbelieved to play a particularly important role in regulating immune andinflammatory responses is the integrin family. This family of cellsurface glycoproteins has a typical non-covalently linked heterodimerstructure. At least 16 different integrin alpha chains and 8 differentintegrin beta chains have been identified [Newman, P. et al, MolecularMedicine Today, 304, (1996)]. The members of the family are typicallynamed according to their heterodimer composition although trivialnomenclature is widespread in the field. Thus the integrin α4β1 consistsof the integrin alpha 4 chain associated with the integrin beta 1 chain,but is also widely referred to as Very Late Antigen 4 or VLA-4. Not allof the potential pairings of integrin alpha and beta chains have yetbeen observed in nature and the integrin family has been subdivided intoa number of subgroups based on the pairings that have been recognised todate [Sonnenberg, A., Current Topics in Microbiology and Immunology,184, 7, (1993)].

The importance of integrin function in normal physiological responses ishighlighted by two human deficiency diseases in which integrin functionis defective. Thus in the disease termed Leukocyte Adhesion Deficiency(LAD) there is a defect in one of the families of integrins expressed onleukocytes [Marlin, S. D. et al, J. Exp. Med. 164, 855, (1986)].Patients suffering from this disease have a reduced ability to recruitleukocytes to inflammatory sites and suffer recurrent infections, whichin extreme cases may be fatal. In the case of patients suffering fromthe disease termed Glanzman's thrombasthenia (a defect in a member ofthe beta 3 integrin family) there is a defect in blood clotting(Hodivala-Dilke, K. M., J. Clin. Invest. 103, 229, (1999)].

The potential to modify integrin function in such a way as tobeneficially modulate cell adhesion has been extensively investigated inanimal models using specific antibodies and peptides that block variousfunctions of these molecules [e.g. Issekutz, T. B., J. Immunol. 149,3394, (1992); Li, Z. et al, Am. J. Physiol. 263, L723, (1992); Mitjans,F. et al, J. Cell Sci. 108, 2825, (1995); Brooks, P. C. et al, J. Clin.Invest. 96, 1815, (1995); Binns, R. M. et al, J. Immunol. 157, 4094,(1996); Hammes, H.-P. et al, Nature Medicine 2, 529, (1996); Srivata, S.et al, Cardiovascular Res. 36, 408 (1997)]. In particular an antiα₄β₇-antibody has demonstrated both clinical and histologic improvementof inflammatory activity and disease in a non-human primate model ofinflammatory bowel disease [Hesterberg, P. E. et al, Gastroenterol, 111,1373-80 (1996)]. A number of monoclonal antibodies which block integrinfunction are currently being investigated for their therapeuticpotential in human disease, and one, ReoPro, a chimeric antibody againstthe platelet integrin αllbβ3 is in use as a potent anti-thrombotic agentfor use in patients with cardiovascular complications following coronaryangioplasty.

Integrins recognize both cell surface and extracellular matrix ligands,and ligand specificity is determined by the particular alpha-betasubunit combination of the molecule [Newman, P., ibid]. One particularintegrin subgroup of interest involves the α4 chain which can pair withtwo different beta chains β1 and β7 [Sonnenberg, A., ibid]. The α4β1pairing occurs on many circulating leukocytes (for example lymphocytes,monocytes, eosinophils and basophils) although it is absent or onlypresent at low levels on circulating neutrophils. α4β1 binds to anadhesion molecule (Vascular Cell Adhesion Molecule-1 also known asVCAM-1) frequently up-regulated on endothelial cells at sites ofinflammation [Osborne, L., Cell, 62, 3, (1990)]. The molecule has alsobeen shown to bind to at least three sites in the matrix moleculefibronectin [Humphries, M. J. et al, Ciba Foundation Symposium, 189,177,(1995)]. Based on data obtained with monoclonal antibodies in animalmodels it is believed that the interaction between α4β11 and ligands onother cells and the extracellular matrix plays an important role inleukocyte migration and activation [Yednock, T. A. et al, Nature, 356,63, (1992); Podolsky, D. K. et al, J. Clin. Invest. 92, 372, (1993);Abraham, W. M. et al, J. Clin. Invest. 93, 776, (1994)].

The integrin generated by the pairing of α4 and β7 has been termedLPAM-1 [Holzmann, B. and Weissman, I. L., EMBO J. 8, 1735, (1989)]. Theα4β7 pairing is expressed on certain sub-populations of T and Blymphocytes and on eosinophils [Erle, D. J. et al, J. Immunol. 153, 517(1994)]. Like α4β1, α4β7 binds to VCAM-1 and fibronectin. In addition,α4β7 binds to an adhesion molecule believed to be involved in the homingof leukocytes to mucosal tissue such as gastrointestinal mucosa termedMAdCAM-1 [Berlin, C. et al, Cell, 74, 185, (1993)]. MAdCAM-1 ispreferentially expressed in the gastrointestinal track. The interactionbetween α4β7 and MAdCAM-1 may also be important at sites of inflammationoutside of mucosal tissue [Yang, X.-D. et al, PNAS, 91, 12604, (1994)].

Regions of the peptide sequence recognized by α4β1 and α4β7 when theybind to their ligands have been identified. α4β1 seems to recognise LDV,IDA or REDV peptide sequences in fibronectin and a QIDSP sequence inVCAM-1 [Humphries, M. J. et al, ibid] whilst α4β7 recognises a LDTsequence in MAdCAM-1 [Birskin, M. J. et al, J. Immunol. 156, 719,(1996)]. There have been several reports of inhibitors of theseinteractions being designed from modifications of these short peptidesequences [Cardarelli, P. M. et al, J. Biol. Chem., 269, 18668, (1994);Shorff, H. N. et al, Biorganic Med. Chem. Lett., 6, 2495, (1996);Vanderslice, P. et al, J. Immunol., 158, 1710, (1997)]. It has also beenreported that a short peptide sequence derived from the α4β1 bindingsite in fibronectin can inhibit a contact hypersensitivity reaction in atrinitrochlorobenzene sensitised mouse [Ferguson, T. A., et al, PNAS,88,8072, (1991)].

Since the alpha 4 subgroup of integrins are predominantly expressed onleukocytes their inhibition can be expected to be beneficial in a numberof immune or inflammatory disease states. However, because of theubiquitous distribution and wide range of functions performed by othermembers of the integrin family it is important to be able to identifyselective inhibitors of the alpha 4 subgroup.

We have now found a group of compounds which are potent and selectiveinhibitors of α4 integrins. Members of the group are able to inhibit α4integrins such as α4β1 and/or α4β7 at concentrations at which theygenerally have no or minimal inhibitory action on α integrins of othersubgroups. These compounds possess the additional advantage of goodpharmacokinetic properties, especially low plasma clearance.

Thus according to one aspect of the invention we provide a compound offormula (1):

wherein

-   R¹ is a group Ar¹ L²Ar²Alk in which:-   Ar¹ is an optionally substituted aromatic or heteroaromatic group;-   L² is a covalent bond or a linker atom or group;-   Ar² is an optionally substituted arylene or heteroarylene group;-   and Alk is a chain-   in which R is a carboxylic acid (—CO₂H) or a derivative or biostere    thereof;-   X is an —O— or —S— atom or —N(R²)— group in which:-   R² is a hydrogen atom or a C₁₋₆alkyl group;-   V is an oxygen (O) or sulphur (S) atom;-   R^(x), R^(y) and R^(z) which may be the same or different is each an    atom or group -L¹(Alk¹)_(n)(R³)_(v) in which L¹ is a covalent bond    or a linker atom or group, Alk¹ is an optionally substituted    aliphatic or heteroaliphatic chain, R³ is a hydrogen or halogen atom    or group selected from —OR^(3a) [where R^(3a) is a hydrogen atom or    an optionally substituted straight or branched C₁₋₆alkyl group or    C₃₋₈cycloalkyl group], —SR^(3a), —CN or an optionally substituted    cycloaliphatic, heterocycloaliphatic, polycycloaliphatic,    heteropolycycloaliphatic, aromatic or heteroaromatic group, n is    zero or the integer 1 and v is the integer 1, 2 or 3 provided that    when n is zero and L¹ is a covalent bond v is the integer 1;-   or R^(z) is an atom or group as previously defined and R^(x) and    R^(y) are joined together to form an optionally substituted spiro    linked cycloaliphatic or heterocycloaliphatic group;-   and the salts, solvates, hydrates and N-oxides thereof.

It will be appreciated that compounds of formula (1) may have one ormore chiral centres, and exist as enantiomers or diastereomers. Theinvention is to be understood to extend to all such enantiomers,diastereomers and mixtures thereof, including racemates. Formula (1) andthe formulae hereinafter are intended to represent all individualisomers and mixtures thereof, unless stated or shown otherwise. Inaddition, compounds of formula (1) may exist as tautomers, for exampleketo (CH₂C═O)-enol (CH═CHOH) tautomers. Formula (1) and the formulaehereinafter are intended to represent all individual tautomers andmixtures thereof, unless stated otherwise.

Optionally substituted aromatic groups represented by Ar¹ when presentin the group R¹ include for example optionally substituted monocyclic orbicyclic fused ring C₆₋₁₂aromatic groups, such as phenyl, 1- or2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl groups.

Optionally substituted heteroaromatic groups represented by the groupAr¹ when present in the group R¹ include for example optionallysubstituted C₁₋₉heteroaromatic groups containing for example one, two,three or four heteroatoms selected from oxygen, sulphur or nitrogenatoms. In general, the heteroaromatic groups may be for examplemonocyclic or bicyclic fused ring heteroaromatic groups. Monocyclicheteroaromatic groups include for example five- or six-memberedheteroaromatic groups containing one, two, three or four heteroatomsselected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromaticgroups include for example eight- to thirteen-membered fused-ringheteroaromatic groups containing one, two or more heteroatoms selectedfrom oxygen, sulphur or nitrogen atoms.

Particular examples of heteroaromatic groups of these types includepyrrolyl, furyl, thienyl, imidazolyl, N—C₁₋₆alkylimidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl,[2,3-dihydro]benzothienyl, benzothienyl, benzotriazolyl, indolyl,isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,benzoxazolyl, benzisoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl,quinazolinyl, quinoxalinyl, naphthyridinyl, e.g. 2,6-naphthyridinyl, or2,7-naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl,pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl,5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydro-isoquinolinyl, andimidyl, e.g. succinimidyl, phthalimidyl, or naphthalimidyl such as1,8-naphthalimidyl.

Each aromatic or heteroaromatic group represented by the group Ar¹ maybe optionally substituted on any available carbon or, when present,nitrogen atom. One, two, three or more of the same or differentsubstituents may be present and each substituent may be selected forexample from an atom or group -L³(Alk²)_(t)L⁴(R⁴)_(u) in which L³ andL⁴, which may be the same or different, is each a covalent bond or alinker atom or group, t is zero or the integer 1, u is an integer 1, 2or 3, Alk² is an optionally substituted aliphatic or heteroaliphaticchain and R⁴ is a hydrogen or halogen atom or a group selected fromoptionally substituted C₁₋₆alkyl or C₃₋₈cycloalkyl, —OR⁵ [where R⁵ is ahydrogen atom, an optionally substitued C₁₋₆alkyl or C₃₋₈cycloalkylgroup], —SR⁵, —NR⁵R⁶ [where R⁶ is as just defined for R⁵ and may be thesame or different], —NO₂, —CN, —CO₂R⁵, —SO₃H, —SOR⁵, —SO₂R⁵, —SO₃R⁵,—OCO₂R⁵, —CONR⁵R⁶, —OCONR⁵R⁶, —CSNR⁵R⁶, —COR⁵, —OCOR⁵, —N(R⁵)COR⁶,—N(R⁵)CSR⁶, —SO₂N(R⁵)(R⁶), —N(R⁵)SO₂R⁶, N(R⁵)CON(R⁶)(R⁷) [where R⁷ is ahydrogen atom, an optionally substituted C₁₋₆alkyl or C₃₋₈cycloalkylgroup], —N(R⁵)CSN(R⁶)(R⁷) or —N(R⁵)SO₂N(R⁶)(R⁷), provided that when t iszero and each of L³ and L⁴ is a covalent bond then u is the integer 1and R⁴ is other than a hydrogen atom.

When L³ and/or L⁴ is present in these substituents as a linker atom orgroup it may be any divalent linking atom or group. Particular examplesinclude —O— or —S— atoms or —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—,—S(O)₂—, —N(R⁸)— [where R⁸ is a hydrogen atom or an optionallysubstituted straight or branched C₁₋₆alkyl group], —CON(R⁸)—,—OC(O)N(R⁸)—, —CSN(R⁸)—, —N(R⁸)CO—, —N(R⁸)C(O)O—, —N(R⁸)CS—,—S(O)₂N(R⁸)—, —N(R⁸)S(O)₂—, —N(R⁸)O—, —ON(R⁸)—, —N(R⁸)N(R⁸)—,—N(R⁸)CON(R⁸)—, —N(R⁸)CSN(R⁸)—, or —N(R⁸)SO₂N(R⁸)— groups. Where thelinker group contains two R⁸ substituents, these may be the same ordifferent.

When R^(3a), R⁴, R⁵, R⁶, R⁷ and/or R⁸ is present as a C₁₋₆alkyl group itmay be a straight or branched C₁₋₆alkyl group, e.g. a C₁₋₃alkyl groupsuch as a methyl, ethyl or i-propyl group. C₃₋₈cycloalkyl groupsrepresented by R^(3a), R⁴, R⁵, R⁶ and/or R⁷ include C₃₋₆cycloalkylgroups e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.Optional substituents which may be present on such alkyl or cycloalkylgroups include for example one, two or three substituents which may bethe same or different selected from halogen atoms, for example fluorine,chlorine, bromine or iodine atoms, or hydroxy or C₁₋₆alkoxy e.g. methoxyor ethoxy groups.

When the groups R⁵ and R⁶ or R⁶ and R⁷ are both C₁₋₆alkyl groups thesegroups may be joined, together with the N atom to which they areattached, to form a heterocyclic ring. Such heterocyclic rings may beoptionally interrupted by a further heteroatom selected from —O—, —S— or—N(R⁵)—. Particular examples of such heterocyclic rings includepiperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyland piperazinyl rings.

When Alk² is present as an optionally substituted aliphatic orheteroaliphatic chain it may be any optionally substituted aliphatic orheteroaliphatic chain as described hereinafter for Alk¹.

Halogen atoms represented by R⁴ in the optional Ar¹ substituents includefluorine, chlorine, bromine, or iodine atoms.

Examples of the substituents represented by -L³(Alk¹)_(t)L⁴(R⁴)_(u) whenpresent in Ar¹ groups in compounds of the invention include atoms orgroups -L³Alk²L⁴R⁴, -L³Alk²R⁴, -L³R⁴, —R⁴ and -Alk²R⁴ wherein L³, Alk²,L⁴ and R⁴ are as defined above. Particular examples of such substituentsinclude -L³CH₂L⁴R⁴, -L³CH(CH₃)L⁴R⁴, -L³(CH₂)₂L⁴R⁴, -L³CH₂R⁴,-L³CH(CH₃)R⁴, -L³(CH₂)₂R⁴, —CH₂R⁴, —CH(CH₃)R⁴, —(CH₂)₂R⁴ and —R⁴ groups.

Thus Ar¹ in compounds of the invention may be optionally substituted forexample by one, two, three or more halogen atoms, e.g. fluorine,chlorine, bromine or iodine atoms, and/or C₁₋₆alkyl, e.g. methyl, ethyl,n-propyl, i-propyl, n-butyl or t-butyl, C₃₋₈cycloalkyl, e.g.cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, C₁₋₆hydroxyalkyl,e.g. hydroxymethyl, hydroxyethyl or —C(OH)(CF₃)₂, carboxyC₁₋₆alkyl, e.g.carboxyethyl, C₁₋₆alkylthio e.g. methylthio or ethylthio,carboxyC₁₋₆alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or3-carboxypropylthio, C₁₋₆alkoxy, e.g. methoxy or ethoxy,hydroxyC₁₋₆alkoxy, e.g. 2-hydroxyethoxy, haloC₁₋₆alkyl, e.g. —CF₃,—CHF₂, —CH₂F, haloC₁₋₆alkoxy, e.g. —OCF₃, —OCHF₂, —OCH₂F,C₁₋₆alkylamino, e.g. methylamino or ethylamino, amino (—NH₂),aminoC₁₋₆alkyl, e.g. aminomethyl or aminoethyl, C₁₋₆dialkylamino, e.g.dimethylamino or diethylamino, C₁₋₆alkylaminoC₁₋₆alkyl, e.g.ethylaminoethyl, C₁₋₆dialkylaminoC₁₋₆alkyl, e.g. diethylaminoethyl,aminoC₁₋₆alkoxy, e.g. aminoethoxy, C₁₋₆alkylaminoC₁₋₆alkoxy, e.g.methylaminoethoxy, C₁₋₆dialkylaminoC₁₋₆alkoxy, e.g. dimethylaminoethoxy,diethylaminoethoxy, diisopropylaminoethoxy or dimethylaminopropoxy,nitro, cyano, amidino, hydroxyl (—OH), formyl [HC(O)—], carboxyl(—CO₂H), —CO₂R⁵ e.g. —CO₂CH₃ or —CO₂C(CH₃)₃, C₁₋₆alkanoyl e.g. acetyl,thiol (—SH), thioC₁₋₆alkyl, e.g. thiomethyl or thioethyl, sulphonyl(—SO₃H), —SO₃R⁵, C₁₋₆alkylsulphinyl, e.g. methylsulphinyl,C₁₋₆alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (—SO₂NH₂),C₁₋₆alkylaminosulphonyl, e.g. methylaminosulphonyl orethylaminosulphonyl, C₁₋₆dialkylaminosulphonyl, e.g.dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl,carboxamido (—CONH₂), C₁₋₆alkylaminocarbonyl, e.g. methylaminocarbonylor ethylaminocarbonyl, C₁₋₆dialkylaminocarbonyl, e.g.dimethylaminocarbonyl or diethylaminocarbonyl,aminoC₁₋₆alkylaminocarbonyl, e.g. aminoethylaminocarbonyl,C₁₋₆alkylaminoC₁₋₆alkylaminocarbonyl, e.g. ethylaminoethylaminocarbonyl,C₁₋₆dialkylaminoC₁₋₆alkylaminocarbonyl, e.g.diethylaminoethylaminocarbonyl, aminocarbonylamino,C₁₋₆alkylaminocarbonylamino, e.g. methylaminocarbonylamino orethylaminocarbonylamino, C₁₋₆dialkylaminocarbonylamino, e.g.dimethylaminocarbonylamino or diethylaminocarbonylamino,C₁₋₆alkylaminocabonylC₁₋₆alkylamino, e.g.methylaminocarbonylmethylamino, aminothiocarbonylamino,C₁₋₆alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino orethylaminothiocarbonylamino, C₁₋₆dialkylaminothiocarbonylamino, e.g.dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino,C₁₋₆alkylaminothiocarbonylC₁₋₆alkylamino, e.g.ethylaminothiocarbonylmethylamino, C₁₋₆alkylsulphonylamino, e.g.methylsulphonylamino or ethylsulphonylamino, C₁₋₆dialkylsulphonylamino,e.g. dimethylsulphonylamino or diethylsulphonylamino,aminosulphonylamino (—NHSO₂NH₂), C₁₋₆alkylaminosulphonylamino, e.g.methylaminosulphonylamino or ethylaminosulphonylamino,C₁₋₆dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino ordiethylaminosulphonylamino, C₁₋₆alkanoylamino, e.g. acetylamino,aminoC₁₋₆alkanoylamino e.g. aminoacetylamino,C₁₋₆dialkylaminoC₁₋₆alkanoylamino, e.g. dimethylaminoacetylamino,C₁₋₆alkanoylaminoC₁₋₆alkyl, e.g. acetylaminomethyl,C₁₋₆alkanoylaminoC₁₋₆alkylamino, e.g. acetamidoethylamino,C₁₋₆alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylaminoor t-butoxycarbonylamino groups.

L² when present as part of the group R¹ in compounds of the inventionmay be a linker atom or group L^(2a) or a linker -(Alk³)L^(2a)-, whereAlk³ is an optionally substituted aliphatic or heteroaliphatic chainwhich may be any such chain as described hereinafter for Alk¹, andL^(2a) may be any linker atom or group as described hereinbefore for L³.

Optionally substituted arylene groups represented by Ar² when present aspart of the group R¹ include those aromatic groups as previouslydescribed for Ar¹.

Optionally substituted heteroarylene groups represented by Ar² whenpresent as part of the group R¹ include those heteroaromatic groups aspreviously described for Ar¹.

Each divalent arylene or heteroarylene group represented by Ar² may beattached to the remainder of the molecule through any available ringcarbon or nitrogen atoms.

The arylene and heteroarylene groups represented by Ar² may beoptionally substituted by one, two or more substituents selected fromthe atoms or groups -L³(Alk²)_(t)L⁴(R⁴)_(u) described herein. Where twoof these atoms or groups are present they may be the same or different.

When the group R² is present in compounds of the invention as aC₁₋₆alkyl group it may be for example a straight or branched C₁₋₆alkylgroup e.g. a C₁₋₃alkyl group such as a methyl or ethyl group.

When the group R is present in R¹ in compounds of the invention as aderivative of a carboxylic acid it may be for example an acyclic orcyclic carboxylic acid ester or an amide. Particular acyclic esters andamides include —CO₂Alk⁷ and —CONR⁵R⁶ groups as defined herein. When R isa biostere of a carboxylic acid it may be for example a tetrazole orother acid such as phosphonic acid, phosphinic acid, sulphonic acid,sulphinic acid or boronic acid or an acylsulphonamide group.

Esters (—CO₂Alk⁷) and amide (—CONR⁵R⁶) derivatives of the carboxylicacid group (—CO₂H) in compounds of formula (1) may advantageously beused as prodrugs of the active compound. Such prodrugs are compoundswhich undergo biotransformation to the corresponding carboxylic acidprior to exhibiting their pharmacological effects and the inventionparticularly extends to prodrugs of the acids of formula (1). Suchprodrugs are well known in the art, see for example International PatentApplication No. WO00/23419, Bodor, N. (Alfred Benzon Symposium, 1982,17, 156-177), Singh, G. et al (J. Sci. Ind. Res., 1996, 55, 497-510) andBundgaard, H., (Design of Prodrugs, 1985, Elsevier, Amsterdam). 177),Esterified carboxyl groups represented by the group —CO₂Alk⁷ includegroups wherein Alk⁷ is a straight or branched optionally substitutedC₁₋₈alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, t-butyl, pentyl or neopentyl group; an optionallysubstituted C₂₋₈alkenyl group such as a propenyl e.g. 2-propenyl orbutenyl e.g. 2-butenyl or 3-butenyl group, an optionally substitutedC₂₋₈alkynyl group such as a ethynyl, propynyl e.g. 2-propynyl or butynyle.g. 2-butynyl or 3-butynyl group, an optionally substitutedC₃₋₈cycloalkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl group; an optionally substitutedC₃₋₈heterocycloalkyl group such as a tetrahydrofuanyl e.g.tetrahydrofuran-3-yl, pyrrolidinyl e.g. 1-methylpyrrolidinyl such as1-methylpyrrolidin-3-yl, piperidinyl e.g. 1-methylpiperidinyl such as1-methylpiperidin-4-yl, tetrahydropyranyl e.g. tetrahydropyran-4-yl or2-oxo-[1,3]dioxol-4-yl e.g. 5-methyl-2-oxo-[1,3]dioxol-4-yl group; anoptionally substituted C₃₋₈cycloalkylC₁₋₈alkyl group such as acyclopentylmethyl, cyclohexylmethyl or cyclohexylethyl group; anoptionally substituted C₃₋₈heterocycloalkylC₁₋₈alkyl group such as amorpholinyl-N-ethyl, thiomorpholinyl-N-methyl, pyrrolidinyl-N-ethyl,pyrrolidinyl-N-propyl, piperidinyl-N-ethyl, pyrazolidinyl-N-methyl orpiperazinyl-N-ethyl group; an optionally substitutedC₁₋₆alkyloxyC₁₋₆alkyl group such as a methyloxyethyl or propyloxyethylgroup; an optionally substituted hydroxyC₁₋₆alkyl group such as ahydroxyethyl e.g. 2-hydroxyethyl or hydroxypropyl e.g. 2-hydroxypropyl,3-hydroxypropyl or 2,3-dihydroxypropyl group; an optionally substitutedC₁₋₆alkylthioC₁₋₆alkyl group such as an ethylthioethyl group; anoptionally substituted C₁₋₆alkylsulfinylC₁₋₆alkyl group such as anmethylsulfinylethyl group; an optionally substitutedC₁₋₆alkylsulfonylC₁₋₆alkyl group such as an methylsulfonylmethyl group;an optionally substituted C₃₋₈cycloalkyloxyC₁₋₆alkyl group such as acyclohexyloxymethyl group; an optionally substitutedC₃₋₈cycloalkylthioC₁₋₆alkyl group such as a cyclopentylthiomethyl group;an optionally substituted C₃₋₈cycloalkylsulfinylC₁₋₆alkyl group such asa cyclopentyl-sulfinylmethyl group; an optionally substitutedC₃₋₈cycloalkylsulfonylC₁₋₆alkyl group such as acyclopentylsulfonylmethyl group; an optionally substitutedC₁₋₆alkyloxycarbonylC₁₋₆alkyl group such as isobutoxy-carbonylpropylgroup; an optionally substituted C₁₋₆alkyloxycarbonylC₁₋₆alkenyl groupsuch as isobutoxycarbonylpentenyl group; an optionally substitutedC₁₋₆alkyloxycarbonyloxyC₁₋₆alkyl group such as anethyloxycarbonyloxymethyl or isopropoxycarbonyloxyethyl e.g1-(isopropoxycarbonyloxy)ethyl or 2-(isopropoxycarbonyloxy)ethyl group;an optionally substituted C₁₋₆alkyloxycarbonyloxyC₁₋₆alkenyl group suchas a isopropoxycarbonyloxybutenyl group, an optionally substitutedC₃₋₈cycloalkyloxycarbonyloxyC₁₋₆alkyl group such as acyclohexyloxycarbonyloxyethyl, e.g. a 2-(cyclohexyloxycarbonyloxy)ethylgroup, an optionally substituted N-di-C₁₋₈alkylaminoC₁₋₈alkyl group suchas a N-dimethylaminoethyl or N-diethylaminoethyl group; an optionallysubstituted N—C₆₋₁₂aryl-N—C₁₋₆alkylaminoC₁₋₆alkyl group such as aN-phenyl-N-methylaminomethyl group; an optionally substitutedN-di-C₁₋₈alkyl-carbamoylC₁₋₈alkyl group such as aN-diethylcarbamoylmethyl group; an optionally substitutedC₆₋₁₂arylC₁₋₆alkyl group such as an optionally substituted benzyl,phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group;an optionally substituted heteroC₆₋₁₀arylC₁₋₆alkyl group, such as apyridinylmethyl e.g. pyridin-4-ylmethyl or imidazolylethyl e.g.2-imidazol-1-ylethyl group; a C₆₋₁₂aryl group such as an optionallysubstituted phenyl, 1-naphthyl or 2-naphthyl group; aC₆₋₁₂aryloxyC₁₋₈alkyl group such as an optionally substitutedphenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or2-naphthyloxymethyl group; a C₆₋₁₂arylthioC₁₋₈alkyl group such as anoptionally substituted phenylthioethyl group; aC₆₋₁₂arylsulfinylC₁₋₈alkyl group such as an optionally substitutedphenyl-sulfinylmethyl group; a C₆₋₁₂arylsulfonylC₁₋₈alkyl group such asan optionally substituted phenylsulfonylmethyl group; an optionallysubstituted C₁₋₈alkanoyloxyC₁₋₈alkyl group, such as a acetoxymethyl,ethoxycarbonyloxyethyl, pivaloyloxymethyl, propionyloxyethyl orpropionyl-oxypropyl group; an optionally substituted C₄₋₈imidoC₁₋₈alkylgroup such as a succinimidomethyl or phthalamidoethyl group; aC₆₋₁₂aroyloxyC₁₋₈alkyl group such as an optionally substitutedbenzoyloxyethyl or benzoyloxypropyl group or a triglyceride such as a2-substituted triglyceride e.g. a 1,3-di-C₁₋₈alkylglycerol-2-yl groupsuch as a 1,3-diheptylglycerol-2-yl group. Optional substituents presenton the Alk⁷ group include R^(13a) substituents described below.

It will be appreciated that in the forgoing list of Alk⁷ groups thepoint of attachment to the remainder of the compound of formula (1) isvia the last described part of the Alk⁷ group. Thus, for example amethoxyethyl group would be attached by the ethyl group, whilst amorpholinyl-N-ethyl group would be attached via the N-ethyl group.

It will be further appreciated that in the forgoing list of Alk⁷ groups,where not specifically mentioned, alkyl groups may be replaced byalkenyl or alkynyl groups where such groups are as previously definedfor Alk¹. Additionally these alkyl, alkenyl or alkynyl groups mayoptionally be interrupted by one, two or three linker atoms or groupswhere such linker atoms and groups are as previously defined for L³.

Further prodrugs of compounds of formula (1) include cyclic esters whereX is a —N(R²)— group in which R² becomes a C₁₋₆alkyl joining chain,especially a —CH₂— or —CH₂CH₂— chain, which is also connected to theacid group R to form a cyclic ester of formula (1a):

When present in the group R^(x), R^(y) and/or R^(z) in compounds offormula (1) the linker atom or group represented by L¹ may be any linkeratom or group as described above for the linker atom or group L³. Inaddition L¹ may also be a —Se— atom.

When Alk¹ is present in the group R^(x), R^(y) and/or R^(z) in compoundsof formula (1) as an optionally substituted aliphatic chain it may be anoptionally substituted C₁₋₁₀aliphatic chain. Particular examples includeoptionally substituted straight or branched chain C₁₋₆alkylene,C₂₋₆alkenylene or C₂₋₆alkynylene chains.

Particular examples of aliphatic chains represented by Alk¹ includeoptionally substituted —CH₂—, —(CH₂)₂—, —CH(CH₃)CH₂—, —(CH₂)₂CH₂—,—(CH₂)₃CH₂—, —CH(CH₃)(CH₂)₂—, —CH₂CH(CH₃)CH₂—, —C(CH₃)₂CH₂—,—CH₂C(CH₃)₂CH₂—, —(CH₂)₂C(CH₃)₂CH₂—, —(CH₂)₄CH₂—, —(CH₂)₅CH₂—, —CHCH—,—CHCHCH₂—, —CH₂CHCH—, —CHCHCH₂CH₂—, —CH₂CHCHCH₂—, —(CH₂)₂CHCH—, —CC—,—CCCH₂—, —CH₂CC—, —CCCH₂CH₂—, —CH₂CCCH₂— or —(CH₂)₂CC— chains.

Heteroaliphatic chains represented by Alk¹ when present in the groupR^(x), R^(y) and/or R^(z) in compounds of formula (1) include thealiphatic chains just described for Alk¹ but with each additionallycontaining one, two, three or four heteroatoms or heteroatom-containinggroups. Particular hetero-atoms or groups include atoms or groups L⁵where L⁵ is as defined above for L³ when L³ is a linker atom or group.Each L⁵ atom or group may interrupt the aliphatic chain, or may bepositioned at its terminal carbon atom to connect the chain to anadjoining atom or group. Particular examples include optionallysubstituted —CH₂L⁵-, —CH₂CH₂L⁵-, -L⁵CH₂—, -L⁵CH₂CH₂—, -L⁵CH(CH₃)CH₂—,-L⁵CH₂CH(CH₃)CH₂—, -L⁵CH₂CH₂CH(CH₃)—, -L⁵C(CH₃)₂CH₂—, —CH₂L⁵CH₂CH₂—,—(CH₂)₂L⁵CH₂—, —(CH₂)₃L⁵CH₂—, -L⁵(CH₂)₃—, -L⁵(CH₂)₄—, —CH₂L⁵CH₂CHL⁵CH₂—and —(CH₂)₂L⁵CH₂CH₂— chains.

The optional substituents which may be present on aliphatic orheteroaliphatic chains represented by Alk¹ include one, two, three ormore substituents where each substituent may be the same or differentand is selected from halogen atoms, e.g. fluorine, chlorine, bromine oriodine atoms, or —OH, —CO₂H, —CO₂R⁹, where R⁹ is an optionallysubstituted straight or branched C₁₋₆alkyl group as defined above forR⁴, —CONHR⁹, —CON(R⁹)₂, —COR⁹, e.g. —COCH₃, C₁₋₆alkoxy, e.g. methoxy orethoxy, thiol, —S(O)R⁹, —S(O)₂R⁹, C₁₋₆alkylthio e.g. methylthio orethylthio, amino or substituted amino groups. Substituted amino groupsinclude —NHR⁹ and —N(R⁹)₂ groups. Where two R⁹ groups are present in anyof the above substituents these may be the same or different.

Optionally substituted cycloaliphatic groups represented by the group R³when present in the group R^(x), R^(y) and/or R^(z) in compounds of theinvention include optionally substituted C₃₋₁₀cycloaliphatic groups.Particular examples include optionally substituted C₃₋₁₀cycloalkyl, e.g.C₃₋₈cycloalkyl or C₃₋₁₀cycloalkenyl, e.g C₃₋₈cycloalkenyl groups.

Optionally substituted heterocycloaliphatic groups represented by thegroup R³ when present in the group R^(x), R^(y) and/or R^(z) includeoptionally substituted C₃₋₁₀heterocycloaliphatic groups. Particularexamples include optionally substituted C₃₋₁₀heterocycloalkyl, e.g.C₃₋₇heterocycloalkyl, or C₃₋₁₀heterocycloalkenyl, e.g.C₃₋₇hetercycloalkenyl groups, each of said groups containing one, two,three or four heteroatoms or heteroatom-containing groups L⁵ as definedabove.

Optionally substituted polycycloaliphatic groups represented by thegroup R³ when present in the group R^(x), R^(y) and/or R^(z) includeoptionally substitued C₇₋₁₀ bi- or tricycloalkyl or C₇₋₁₀bi- ortricycloalkenyl groups. Optionally substituted heteropolycycloaliphaticgroups represented by the group R³ include the optionally substitutedpolycycloaliphatic groups just described, but with each groupadditionally containing one, two, three or four L⁵ atoms or groups.

Particular examples of cycloaliphatic, polycycloaliphatic,heterocyclo-aliphatic and heteropolycycloaliphatic groups represented bythe group R³ include optionally substituted cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, adamantyl,norbornyl, norbornenyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydrothiophene-1-oxide, tetrahydrothiophene-1,1-dioxide, pyrroline,e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl,oxazolidinone, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g.2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl,pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide,tetrahydrothiopyran-1,1-dioxide, piperidinyl, piperidinone, dioxanyle.g. 1,3-dioxanyl or 1,4-dioxanyl, morpholinyl, morpholinone, dithianyl,e.g. 1,3-dithianyl or 1,4-dithianyl, thiomorpholinyl, piperazinyl,1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or4H-1,4- oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, e.g. o- orp-isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or1,3,5,-oxadiazinyl groups.

The optional substituents which may be present on the cycloaliphatic,polycycloaliphatic, heterocycloaliphatic or heteropolycycloaliphaticgroups represented by the group R³ include one, two, three or moresubstituents each selected from halogen atoms, e.g. fluorine, chlorine,bromine or iodine atoms, or C₁₋₆alkyl, e.g. methyl, ethyl, propyl ori-propyl, haloC₁₋₆alkyl, e.g. halomethyl or haloethyl such asdifluoromethyl or trifluoromethyl, optionally substituted by hydroxyl,e.g. —C(OH)(CF₃)₂, C₁₋₆alkoxy, e.g. methoxy, ethoxy or propoxy,haloC₁₋₆alkoxy, e.g. halomethoxy or haloethoxy such as difluoromethoxyor trifluoromethoxy, thiol, C₁₋₆alkylthio e.g. methylthio, ethylthio orpropylthio, or -(Alk⁴)_(g)R¹⁰ groups in which Alk⁴ is a straight orbranched C₁₋₃alkylene chain, g is zero or an integer 1 and R¹⁰ is a —OH,—SH, —N(R¹¹)₂, (in which R¹¹ is an atom or group as defined herein forR⁷) —CN, —CO₂R¹¹, —NO₂, —CON(R¹¹)₂, —CSN(R¹¹)₂, —COR¹¹, —CSN(R¹¹)₂,—N(R¹¹)COR¹¹, —N(R¹¹)CSR¹¹, —SO₂N(R¹¹)₂, —N(R¹¹)SO₂R¹¹,—N(R¹¹)CON(R¹¹)₂, —N(R¹¹)CSN(R¹¹), N(R¹¹)SO₂N(R¹¹)₂ or optionallysubstituted phenyl group. Where two R¹¹ atoms or groups are present inthese substituents these may be the same or different or joined to forma heterocyclic ring as previously described when R⁵ and R⁶ are joinedtogether. Optionally substituted phenyl groups include phenylsubstituted by one, two or three of the R¹³ groups described below.

Additionally, when the group R³ is a heterocycloaliphatic groupcontaining one or more nitrogen atoms each nitrogen atom may beoptionally substituted by a group -(L⁶)_(p)(Alk⁵)_(q)R¹² in which L⁶ is—C(O)—, —C(O)O—, —C(S)—, —S(O)₂—, —CON(R⁸)—, —CSN(R⁸)— or SO₂N(R⁸)—; pis zero or an integer 1; Alk⁵ is an optionally substituted aliphatic orheteroaliphatic chain; q is zero or an integer 1; and R¹² is a hydrogenatom or an optionally substituted cycloaliphatic, heterocycloaliphatic,polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromaticgroup.

C₁₋₃alkylene chains represented by Alk⁴ include —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH(CH₃)CH₂— and —CH₂CH(CH₃)— chains.

Optionally substituted aliphatic or heteroaliphatic chains representedby Alk⁵ include those optionally substituted chains described above forAlk¹. Optional substituents which may be present on these groups includethose described above in relation to Alk¹.

Cycloaliphatic, heterocycloaliphatic, polycycloaliphatic orpolyheterocycloaliphatic groups represented by R¹² include those groupsjust described for the group R³. Optional substituents which may bepresent on those groups include those described above in relation to R³cycloaliphatic groups.

Aromatic or heteroaromatic groups represented by R¹² include thosegroups described herein for the group Ar¹. Optional substituents whichmay be present on these groups include those R¹³ optional substituentsdescribed hereinafter.

When the group R³ is an optionally substituted aromatic orheteroaromatic group it may be for example an aromatic or heteroaromaticgroup as described herein for the group Ar¹.

Optional substituents which may be present on the aromatic orheteroaromatic groups represented by the group R³ include one, two,three or more substituents, each selected from an atom or group R¹³ inwhich R¹³ is —R^(13a) or -Alk⁶(R^(13a))_(m), where R^(13a) is a halogenatom, or an amino (—NH₂), substituted amino, nitro, cyano, amidino,hydroxyl (—OH), substituted hydroxyl, formyl, carboxyl (—CO₂H),esterified carboxyl, thiol (—SH), substituted thiol, —COR¹⁴ [where R¹⁴is an -Alk⁶(R^(13a))_(m), aryl or heteroaryl group], —CSR¹⁴, —SO₃H,—SOR¹⁴, —SO₂R¹⁴, —SO₃R¹⁴, —SO₂NH₂, —SO₂NHR¹⁴, SO₂N(R¹⁴)₂, —CONH₂,—CSNH₂, —CONHR¹⁴, —CSNHR¹⁴, —CON[R¹⁴]₂, —CSN(R¹⁴)₂, —N(R¹¹)SO₂R¹⁴,—N(SO₂R¹⁴)₂, —NH(R¹¹)SO₂NH₂, —N(R¹¹)SO₂NHR¹⁴, —N(R¹¹)SO₂N(R¹⁴)₂,—N(R¹¹)COR¹⁴, —N(R¹¹)CONH₂, —N(R¹¹)CONHR¹⁴, —N(R¹¹)CON(R¹⁴)₂,—N(R¹¹)CSNH₂, —N(R¹¹)CSNHR¹⁴, —N(R¹¹)CSN(R¹⁴)₂, —N(R¹¹)CSR¹⁴,—N(R¹¹)C(O)OR¹⁴, —SO₂NHet¹ [where —Nhet¹ is an optionally substitutedC₅₋₇cyclicamino group optionally containing one or more other —O— or —S—atoms or —N(R¹¹)—, —C(O)—, —C(S)—, S(O) or —S(O)₂ groups], —CONHet¹,—CSNhet¹, —N(R¹¹)SO₂NHet¹, —N(R¹¹)CONHet¹, —N(R¹¹)CSNHet¹,—SO₂N(R¹¹)Het² [where Het² is an optionally substituted monocyclicC₅₋₇carbocyclic group optionally containing one or more —O— or —S— atomsor —N(R¹¹)—, —C(O)— or —C(S)— groups], -Het², —CON(R¹¹)Het²,—CSN(R¹¹)Het², —N(R¹¹)CON(R¹¹)Het², —N(R¹¹)CSN(R¹¹)Het², aryl orheteroaryl group; Alk⁶ is a straight or branched C₁₋₆alkylene,C₂₋₆alkenylene or C₂₋₆alkynylene chain, optionally interrupted by one,two or three —O— or —S— atoms or —S(O)_(n) [where n is an integer 1 or2] or —N(R¹⁵)— groups [where R¹⁵ is a hydrogen atom or C₁₋₆alkyl, e.g.methyl or ethyl group]; and m is zero or an integer 1, 2 or 3. It willbe appreciated that when two R¹¹ or R¹⁴ groups are present in one of theabove substituents, the R¹¹ or R¹⁴ groups may be the same or different.

When in the group -Alk⁶(R^(13a))_(m) m is an integer 1, 2 or 3, it is tobe understood that the substituent or substituents R^(13a) may bepresent on any suitable carbon atom in -Alk⁶. Where more than oneR^(13a) substituent is present these may be the same or different andmay be present on the same or different atom in -Alk⁶. Clearly, when mis zero and no substituent R^(13a) is present the alkylene, alkenyleneor alkynylene chain represented by Alk⁶ becomes an alkyl, alkenyl oralkynyl group.

When R^(13a) is a substituted amino group it may be for example a group—NHR¹⁴ [where R¹⁴ is as defined above] or a group —N(R¹⁴)₂ wherein eachR¹⁴ group is the same or different.

When R^(13a) is a halogen atom it may be for example a fluorine,chlorine, bromine, or iodine atom.

When R^(13a) is a substituted hydroxyl or substituted thiol group it maybe for example a group —OR¹⁴ or a —SR¹⁴ or —SC(═NH)NH₂ grouprespectively.

Esterified carboxyl groups represented by the group R^(13a) includegroups of formula —CO₂Alk⁸ wherein Alk⁸ is a straight or branched,optionally substituted C₁₋₈alkyl group such as a methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; aC₆₋₁₂arylC₁₋₈alkyl group such as an optionally substituted benzyl,phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; aC₆₋₁₂aryl group such as an optionally substituted phenyl, 1-naphthyl or2-naphthyl group; a C₆₋₁₂aryloxyC₁₋₈alkyl group such as an optionallysubstituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or2-naphthyloxymethyl group; an optionally substitutedC₁₋₈alkanoyloxyC₁₋₈alkyl group, such as a pivaloyloxymethyl,propionyloxyethyl or propionyloxypropyl group; or aC₆₋₁₂aroyloxyC₁₋₈alkyl group such as an optionally substitutedbenzoyloxyethyl or benzoyloxy-propyl group. Optional substituentspresent on the Alk⁸ group include R^(13a) substituents described above.

When Alk⁶ is present in or as a substituent it may be for example amethylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene,s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene,3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylenechain, optionally interrupted by one, two, or three —O— or —S—, atoms or—S(O)—, —S(O)₂— or —N(R⁸)— groups.

Aryl or heteroaryl groups represented by the groups R^(13a) or R¹⁴include mono- or bicyclic optionally substituted C₆₋₁₂aromatic orC₁₋₉heteroaromatic groups as described above for the group Ar¹. Thearomatic and heteroaromatic groups may be attached to the remainder ofthe compound of formula (1) by any carbon or hetero e.g. nitrogen atomas appropriate.

When —NHet¹ or -Het² forms part of a substituent R¹³ each may be forexample an optionally substituted pyrrolidinyl, pyrazolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinylgroup. Additionally Het² may represent for example, an optionallysubstituted cyclopentyl or cyclohexyl group. Optional substituents whichmay be present on —NHet¹ or -Het² include those optional substituentsdescribed above in relation to aliphatic chains represented by Alk¹.

Particularly useful atoms or groups represented by R¹³ include fluorine,chlorine, bromine or iodine atoms, or C₁₋₆alkyl, e.g. methyl, ethyl,n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl,pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl,thiomorpholinyl, piperazinyl, e.g. t-butyloxycarbonylpiperazinyl,pyrrolidinyl, dioxolanyl, dioxanyl, oxazolidinyl, thiazolidinyl,imidazolidinyl or piperidinyl, C₁₋₆hydroxyalkyl, e.g. hydroxymethyl orhydroxyethyl, carboxyC₁₋₆alkyl, e.g. carboxyethyl, C₁₋₆alkylthio e.g.methylthio or ethylthio, carboxyC₁₋₆alkylthio, e.g. carboxymethylthio,2-carboxyethylthio or 3-carboxypropylthio, C₁₋₆alkoxy, e.g. methoxy orethoxy, hydroxyC₁₋₆alkoxy, e.g. 2-hydroxyethoxy, optionally substitutedphenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio,C₄₋₇cycloalkyl, e.g. cyclobutyl, cyclopentyl, C₅₋₇cycloalkoxy, e.g.cyclopentyloxy, haloC₁₋₆alkyl, e.g. trifluoromethyl, haloC₁₋₆alkoxy,e.g. trifluoromethoxy, C₁₋₆alkylamino, e.g. methylamino, ethylamino orpropylamino, C₆₋₁₂arylC₁₋₆alkylamino, e.g. benzylamino,4-fluorobenzylamino or 4-hydroxyphenylethylamino, amino (—NH₂),aminoC₁₋₆alkyl, e.g. aminomethyl or aminoethyl, C₁₋₆dialkylamino, e.g.dimethylamino or diethylamino, aminoC₁₋₆alkylamino, e.g. aminoethylaminoor amino-propylamino, optionally substituted Het¹NC₁₋₆alkylamino, e.g.3-morpholinopropylamino, C₁₋₆alkylaminoC₁₋₆alkyl, e.g. ethylaminoethyl,C₁₋₆dialkylaminoC₁₋₆alkyl, e.g. diethylaminoethyl, aminoC₁₋₆alkoxy, e.g.aminoethoxy, C₁₋₆alkylaminoC₁₋₆alkoxy, e.g. methylaminoethoxy,C₁₋₆dialkylaminoC₁₋₆alkoxy, e.g. dimethylaminoethoxy,diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy,hydroxyC₁₋₆alkylamino, e.g. 2-hydroxyethylamino, 3-hydroxypropylamino or3-hydroxybutylamino, imido, such as phthalimido or naphthalimido, e.g.1,8-naphthalimido, nitro, cyano, amidino, hydroxyl (—OH), formyl[HC(O)—], carboxyl (—CO₂H), —CO₂Alk⁸ [where Alk⁸ is as defined above],C₁₋₆alkanoyl e.g. acetyl, propyryl or butyryl, optionally substitutedbenzoyl, thiol (—SH), thioC₁₋₆alkyl, e.g. thiomethyl or thioethyl,—SC(═NH)NH₂, sulphonyl (—SO₃H), —SO₃Alk⁸, C₁₋₆alkylsulphinyl, e.g.methylsulphinyl, ethylsulphinyl or propylsulphinyl, C₁₋₆alkylsulphonyl,e.g. methylsulphonyl, ethylsulphonyl or propylsulphonyl, aminosulphonyl(—SO₂NH₂), C₁₋₆alkylaminosulphonyl, e.g. methylaminosulphonyl,ethylaminosulphonyl or propylaminosulphonyl C₁₋₆dialkylaminosulphonyl,e.g. dimethylaminosulphonyl or diethylaminosulphonyl,phenylaminosulphonyl, carboxamido (—CONH₂), C₁₋₆alkylaminocarbonyl, e.g.methylaminocarbonyl, ethylaminocarbonyl or propylaminbcarbonyl,C₁₋₆dialkylaminocarbonyl, e.g. dimethylaminocarbonyl ordiethylaminocarbonyl, aminoC₁₋₆alkylaminocarbonyl, e.g.aminoethylaminocarbonyl, C₁₋₆alkylaminoC₁,₆alkylaminocarbonyl, e.g.methylaminoethylaminocarbonyl, C₁₋₆dialkylaminoC₁₋₆alkylaminocarbonyl,e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino,C₁₋₆alkylaminocarbonylamino, e.g. methylaminocarbonylamino orethylaminocarbonylamino, C₁₋₆dialkylaminocarbonylamino, e.g.dimethylaminocarbonylamino or diethylaminocarbonylamino,C₁₋₆alkylaminocabonylC₁₋₆alkylamino, e.g.methylaminocarbonylmethylamino, aminothiocarbonylamino,C₁₋₆alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino orethylaminothiocarbonylamino, C₁₋₆dialkylaminothiocarbonylamino, e.g.dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino,C₁₋₆alkylaminothiocarbonylC₁₋₆alkylamino, e.g.ethylaminothiocarbonylmethylamino, —CONHC(═NH)NH₂,C₁₋₆alkylsulphonylamino, e.g. methylsulphonylamino orethylsulphonylamino, haloC₁₋₆alkylsulphonylamino, e.g.trifluoromethylsulphonylamino, C₁₋₆dialkylsulphonylamino, e.g.dimethylsulphonylamino or diethylsulphonylamino, optionally substitutedphenylsulphonylamino, aminosulphonylamino (—NHSO₂NH₂),C₁₋₆alkylaminosulphonylamino, e.g. methylaminosulphonylamino orethylaminosulphonylamino, C₁₋₆dialkylaminosulphonylamino, e.g.dimethylaminosulphonylamino or diethylaminosulphonylamino, optionallysubstituted morpholinesulphonylamino ormorpholinesulphonylC₁₋₆alkylamino, optionally substitutedphenylaminosulphonylamino, C₁₋₆alkanoylamino, e.g. acetylamino,aminoC₁₋₆alkanoylamino e.g. aminoacetylamino,C₁₋₆dialkylaminoC₁₋₆alkanoylamino, e.g. dimethylaminoacetylamino,C₁₋₆alkanoylaminoC₁₋₆alkyl, e.g. acetylaminomethyl,C₁₋₆alkanoylaminoC₁₋₆alkylamino, e.g. acetamidoethylamino,C₁₋₆alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylaminoor t-butoxycarbonylamino or optionally substituted benzyloxy,pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino,benzyloxycarbonylaminoC₁₋₆alkyl e.g. benzyloxycarbonylaminoethyl,thiobenzyl, pyridylmethylthio or thiazolylmethylthio groups.

Where desired, two R¹³ substituents may be linked together to form acyclic group such as a cyclic ether, e.g. a C₁₋₆alkylenedioxy group suchas methylenedioxy or ethylenedioxy.

It will be appreciated that where two or more R¹³ substituents arepresent, these need not necessarily be the same atoms and/or groups. Ingeneral, the substituent(s) may be present at any available ringposition in the aromatic or heteroaromatic group represented by R³.

When the groups R^(x) and R^(y) are joined together to form anoptionally substituted spiro linked cycloaliphatic orheterocycloaliphatic group joined to the cyclobutenone ring as definedby formula (1) it may be any such cycloaliphatic or heterocycloaliphaticgroup as previously described for R³. Optional substituents which may bepresent on such spiro linked cycloaliphatic or heteroaliphatic groupsinclude those optional substituents as described in relation to R³.

The presence of certain substituents in the compounds of formula (1) mayenable salts of the compounds to be formed. Suitable salts includepharmaceutically acceptable salts, for example acid addition saltsderived from inorganic or organic acids, and salts derived frominorganic and organic bases.

Acid addition salts include hydrochlorides, hydrobromides, hydroiodides,alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, orisothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates ornapsylates, phosphates, sulphates, hydrogen sulphates, acetates,trifluoroacetates, propionates, citrates, maleates, fumarates,malonates, succinates, lactates, oxalates, tartrates and benzoates.

Salts derived from inorganic or organic bases include alkali metal saltssuch as sodium or potassium salts, alkaline earth metal salts such asmagnesium or calcium salts, and organic amine salts such as morpholine,piperidine, dimethylamine or diethylamine salts.

Particularly useful salts of compounds according to the inventioninclude pharmaceutically acceptable salts, especially acid additionpharmaceutically acceptable salts.

In the compounds according to the invention the group R¹ is preferablyan Ar¹L²Ar²Alk group. In compounds of this type Ar¹ is preferably anoptionally substituted phenyl, monocyclic heteroaromatic or bicyclicheteroaromatic group. Particularly useful monocyclic heteroaromaticgroups are optionally substituted five- or six-membered heteroaromaticgroups as described previously, especially five- or six-memberedheteroaromatic groups containing one or two heteroatoms selected fromoxygen, sulphur or nitrogen atoms. Nitrogen-containing groups areespecially useful, particularly pyridyl or pyrimidinyl groups.Particularly useful substituents present on these monocyclic Ar¹ groupsinclude halogen atoms or alkyl, haloalkyl, —OR⁵, —SR⁵, —NR⁵R⁶, —CO₂H,—CO₂CH₃, —NO₂, —N(R⁵)COR⁶ or —CN groups as described above in relationto the compounds of formula (1). Particularly useful bicyclicheteroaromatic groups represented by Ar¹ include optionally substitutedten-membered fused-ring heteroaromatic groups containing one, two orthree, especially one or two heteroatoms, especially nitrogen atoms.Particular examples include optionally substituted naphthyridinyl,especially 2,6-naphthyridinyl, 2,7-naphthyridinyl, quinolinyl andisoquinolinyl, especially isoquinolin-1-yl groups. Particular optionalsubstituents include those just described for monocyclic heteroaromaticgroups. Additionally, in compounds according to the invention X ispreferably an —N(R²)— group and V is preferably an oxygen atom.

A particularly useful group of compounds according to the invention hasthe formula (2a):

-   wherein —W═ is —CR¹⁸═, —N═ or —N(O)═;-   R¹⁶, R¹⁷ and R¹⁸, which may be the same or different is each a    hydrogen atom or an atom or group -L³(Alk²)_(t)L⁴(R⁴)_(u) in which    L³, Alk², t, L⁴, R⁴ and u are as defined previously;-   L², Ar², Alk, R², R^(x), R^(y) and R^(z) are as defined for formula    (1);-   and the salts, solvates, hydrates and N-oxides thereof.

In one preferred class of compounds of formula (2a) where W is a —CR¹⁸═group R¹⁸ is a hydrogen atom. In another preferred class of compoundsR¹⁸ is a preferred atom or group as hereinafter defined for R¹⁶,especially a C₁₋₆alkoxy, especially a methoxy or ethoxy, group.

In another preferred class of compounds of formula (2a) W is a —N═ or—N(O)═group.

R¹⁶ and R¹⁷ in compounds of formula (2a) is each preferably asparticularly described above for compounds of formula (1), other than ahydrogen atom. Particularly useful R¹⁶ and R¹⁷ substituents includehalogen atoms, especially fluorine or chlorine atoms, or C₁₋₆alkyl,especially methyl, ethyl or isopropyl, haloC₁₋₆alkyl especiallyhalomethyl, most especially —CF₃, —CHF₂ or —CH₂F, C₁₋₆alkoxy especiallymethoxy or etoxy or haloC₁₋₆alkoxy especially halomethoxy, mostespecially —OCF₃, —OCHF₂ or —OCH₂F groups.

A further particularly useful group of compounds according to theinvention has the formula (2b):

-   wherein g is the integer 1, 2, 3 or 4;-   R¹⁶, is an atom or group -L³(Alk²)_(t)L⁴(R⁴)_(u) in which L³, Alk²,    t, L⁴, R⁴ and u are as defined previously;-   L², Ar², Alk, R², R^(x), R^(y) and R^(z) are as defined for formula    (1);-   and the salts, solvates, hydrates and N-oxides thereof.

Particularly useful R¹⁶ substituents when present in compounds offormula (2b) include halogen atoms, especially fluorine, chlorine orbromine atoms, or C₁₋₆alkyl e.g. methyl, ethyl or isopropyl,haloC₁₋₆alkyl, especially halomethyl, most especially —CF₃, C₁₋₆alkoxyl,especially methoxy, haloC₁₋₆alkoxy, especially halomethoxy, mostespecially —OCF₃, —CN, —CO₂CH₃, —NO₂, amino (—NH₂), substituted amino(—NR⁵R⁶) especially —NHCH₃ and —N(CH₃)₂, —N(R⁵)COCH₃, especially—NHCOCH₃ groups or optionally substituted phenyl, furyl, thienyl,imidazolyl, pyridyl and pyrimidinyl groups.

A further particularly useful group of compounds according to theinvention has the formula (2c):

-   wherein R¹⁶, g, L², Ar², Alk, R², R^(x), R^(y) and R^(z) are as    defined for formula (2b);-   and the salts, solvates, hydrates and N-oxides thereof.

Each R¹⁶ atom or group in compounds of formula (2c) may be independentlyselected from an atom or group -L³(Alk²)_(n)L⁴(R⁴)_(u) as previouslyparticularly defined for compounds of formula (2b).

A further particularly useful group of compounds according to theinvention has the formula (2d):

wherein R¹⁶, g, L², Ar², Alk, R², R^(x), R^(y) and R^(z) are as definedfor formula (2b):

-   and the salts, solvates, hydrates and N-oxides thereof.

Each R¹⁶ atom or group in compounds of formula (2d) may be independentlyselected from an atom or group -L³(Alk²)_(t)L⁴(R⁴)_(u) as previouslydefined for compounds of formula (2b).

In one preferred class of compounds of formula (2d) at least one R¹⁶atom or group is present at the 3-position of the isoquinoline ring. Ina preferred group of compounds of this class R¹⁶ is an optionallysubstituted phenyl ring. Optional substituents which may be present onthe phenyl ring include halogen atoms, especially fluorine or chlorineatoms, or C₁₋₆alkyl, especially methyl, ethyl or isopropyl,haloC₁₋₆alkyl especially halomethyl, most especially —CF₃, —CHF₂ or—CH₂F, C₁₋₆alkoxy especially methoxy or etoxy or haloC₁₋₆alkoxyespecially halomethoxy, most especially —OCF₃, —OCHF₂ or —OCH₂F groups.

It will be understood that compounds according to formulae (2a), (2b),(2c) and (2d) include, where applicable, the corresponding hydroxytautomers.

Alk in compounds of the invention is preferably:

or, especially, —CH₂CH(R)—.

In one preferred class of compounds of formulae (1), (2a), (2b), (2c)and (2d) R is a —CO₂H group.

In another prefered class of compounds of formulae formulae (1), (2a),(2b), (2c) and (2d) R is an esterified carboxyl group of formula—CO₂Alk⁷ which may advantageously be used as a prodrug of the activecompound. In this class of compound Alk⁷ is preferably a C₁₋₈alkylgroup, especially a methyl, ethyl, propyl, i-propyl, butyl, t-butyl,pentyl or neopenyl group; an optionally substituted C₃₋₈cycloalkylgroup, especially a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl group; an optionally substituted C₃₋₈heterocycloalkyl groupespecially a tetrahydrofuanyl e.g. tetrahydrofuran-3-yl, pyrrolidinyle.g. 1-methylpyrrolidinyl such as 1-methylpyrrolidin-3-yl, piperidinyle.g. 1-methylpiperidinyl such as 1-methylpiperidin-4-yl,tetrahydropyranyl e.g. tetrahydropyran-4-yl or 2-oxo-[1,3]dioxol-4-yle.g. 5-methyl-2-oxo-[1,3]dioxol-4-yl group; an optionally substitutedC₆₋₁₀aryl group, especially a phenyl group; an optionally substitutedC₆₋₁₀arylC₁₋₆alkyl group, especially a benzyl group; an optionallysubstituted heteroC₆₋₁₀arylC₁₋₆alkyl group, especially apyridinylC₁₋₃alkyl group such as pyridinylmethyl e.g. pyridin-4-ylmethylor pyridinylethyl e.g. pyridine-4-ylethyl or a imidazolylC₁₋₃alkyl groupsuch as imidazolylethyl e.g. 2-imidazol-1-ylethyl or imidazolylpropyle.g. 2-imidazol-1-ylpropyl group; an optionally substitutedhydroxyC₁₋₆alkyl group, especially a hydroxyethyl e.g. 2-hydroxyethyl orhydroxypropyl e.g. 3-hydroxypropyl or 2,3-dihydroxypropyl group; anoptionally substituted C₃₋₈heterocycloalkylC₁₋₆alkyl group, especially amorpholinyl-N-ethyl group; an optionally substitutedN-di-C₁₋₈alkylaminoC₁₋₈alkyl group, especially a N-dimethylaminoethyl orN-diethylaminoethyl group; or an optionally substitutedC₁₋₆alkyloxyC₁₋₆alkyl group, especially a methyloxyethyl group.Especially preferred esterified carboxyl groups include —CO₂CH₃,—CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, —CO₂CH(CH₃)₂ and —CO₂C(CH₃)₃ groups. A mostespecially preferred esterified carboxyl group is—CO₂(hydroxyC₁₋₆alkyl), especially —CO₂CH₂CH₂OH.

In general in compounds of formula (1) when X is a —N(R²) group and inparticular in compounds of formulae (2a), (2b), (2c) and (2d) R² ispreferably a hydrogen atom.

In one preferred class of compounds of formula (2a) L² is preferablyL^(2a) where L^(2a) is a —CON(R⁸)— group [where R⁸ is preferably ahydrogen atom or a C₁3alkyl group], especially a —CONH— group or a-(Alk³)L^(2a)- group, especially a -(Alk³)O— group [where Alk³ ispreferably a C₁₋₃alkyl group], most especially a —CH₂O— group. In thisclass of compounds —W═ is preferably —N═ or —N(O)═. Most preferably W is—N═.

In another preferred class of compounds of formula (2a) L² is preferablya covalent bond. In this class of compounds —W═ is preferably —C(R¹⁸)═,where R¹⁸ is as hereinbefore generally and particularly defined.

In general in compounds of formulae (2b), (2c) and (2d) L² is preferablyL^(2a) where L^(2a) is an —O— atom or —N(R⁸)— group [where R⁸ ispreferably a hydrogen atom or a C₁₋₃alkyl group]. An especially useful—N(R⁸)— group is —NH—.

The group Ar² in compounds of formulae (1), (2a), (2b), (2c) and (2d) ispreferably an optionally substituted phenylene or optionally substitutedpyridinediyl group or formula:

where a and b signify the points of attachment of L² and Alkrespectively.

Most preferably Ar² is an optionally substituted 1,4-phenylene group.

Particularly preferred optional substituents which may be present on Ar²in compounds of the invention include halogen atoms, especialy fluorine,chlorine or bromine atoms, or C₁₋₆alkyl e.g. methyl, ethyl or i-propyl,haloC₁₋₆alkyl especially halomethyl, most especialy —CF₃, C₁₋₆alkoxyespecially methoxy or haloC₁₋₆alkoxy, especially halomethoxy, mostespecially —OCF₃, —CN, —CO₂CH₃, —NO₂, amino (—NH₂), substituted amino(NR⁵R⁶) especially —NHCH₃ and —N(CH₃)₂ and —N(R⁵)COCH₃, especially—NHCOCH₃ groups.

In one generally preferred class of compounds of formulae (1), (2a),(2b), (2c) and (2d) R^(x), R^(y) and/or R^(z) is an optionallysubstituted alkyl group, most preferably an optionally substitutedC₁₋₈alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl,n-heptyl, or n-hexyl group. Particularly preferred optional substituentswhich may be present on such R^(x), R^(y) and/or R^(z) alkyl groupsinclude halogen atoms, especially fluorine or chlorine atoms, C₁₋₆alkoxygroups, especially methoxy, haloC₁₋₆alkoxy groups, especially —OCF₃,—CN, —CO₂CH₃, —NO₂, substituted amino (—NR⁵R⁶) especially —NHCH₃ and—N(CH₃)₂ and optionally substituted phenyl groups where the optionalsubstituents are as herein defined for optional substituents on Ar².

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(z) is a hydrogen atom.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) is a hydrogen atom.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(z) is a halogen atom, especially a fluorine, chlorine,bromine or iodine atom, most especially a chlorine or bromine atom.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(z) is a group -L¹(Alk¹)_(n)R³. In this class ofcompounds L¹ is preferably a covalent bond or an —O—, —S— or —Se— atomor —S(O)— or —N(R⁸)—, especially —NH— or —N(CH₃)— group. Most preferablyL¹ is a —S— atom or —S(O)— group. In this class of compounds R³ ispreferably a hydrogen atom or an optionally substitutedC₃₋₁₀cycloaliphatic, especially C₃₋₇cycloalkyl group, most especially anoptionally substituted cyclopentyl, cyclohexyl or cycloheptyl group; oran optionally substituted C₃₋₁₀heterocycloaliphatic, especiallyC₃₋₇heterocycloalkyl group, most especially an optionally substitutedpiperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, dithianyl orpyrazolidinyl group, or an optionally substituted C₆₋₁₂aromatic group,preferably an optionally substituted phenyl group or an optionallysubstituted C₁₋₉heteroaromatic group, preferably an optionallysubstituted monocyclic C₁₋₉heteroaromatic group, most preferably a 5- or6-membered monocyclic heteroaromatic group containing one, two, three orfour heteroatoms selected from oxygen, sulphur or nitrogen atoms,especially an optionally substituted furyl, thienyl, imidazolyl e.g.1-methylimidazol-2-yl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl orpyrazinyl group. Optional substituents which may be present on suchheterocycloaliphatic groups include those substituents as describedhereinafter when R^(x) and R^(y) are joined to form an optionallysubstituted spiro linked heterocycloaliphatic group. Optionalsubstituents which may be present on such aromatic and heteroaromaticgroups include those substituents as described hereinbefore in relationto R¹⁶ substituents in compounds of formula (2a). In one preferred groupof compounds of this class n is zero. In another preferred group ofcompounds of this class L¹ is a covalent bond and n is zero. In thisgroup of compounds R³ is preferrably an optionally substitutedC₃₋₁₀cycloaliphatic, C₃₋₁₀heterocycloaliphatic, C₆₋₁₂aromatic ormonocyclic C₁₋₉heteroaromatic group as just described. In a furtherpreferred group of compounds of this class n is the integer 1 and Alk¹is preferably an optionally substituted aliphatic chain, most preferablyan optionally substituted C₁₋₆alkylene chain, especially a —CH₂—,—CH₂CH₂— or —CH₂CH(CH₃)— chain. In a further preferred group ofcompounds of this class L¹ is a covalent bond, n is the integer 1 andAlk¹ is preferably an optionally substituted aliphatic chain, mostpreferably an optionally substituted C₁₋₆alkylene chain, especially a—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH(CH₃)— chain. In a furtherpreferred group of compounds of this class L¹ is a preferred atom orgroup as just described, most especially a —S— atom, n is the integer 1and Alk¹ is preferably an optionally substituted aliphatic chain, mostpreferably an optionally substituted C₁₋₆alkylene chain, especially a—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH(CH₃)— chain. In this class ofcompounds R³ is preferably a hydrogen atom.

Most especially useful R^(z) groups which may be present in compounds ofthe invention include a hydrogen or halogen atom, especially fluorine,chlorine, bomine or iodine atom or a group of formula -L¹(Alk¹)_(n)R³ asjust defined, especially an alkyl group as previously described or ahydroxyl (—OH); C₁₋₆alkoxymethoxy, ethoxy or i-propoxy; C₃₋₇cycloalkyl,especially cyclopentyl or cyclohexyl; C₁₋₆alkylsulfanyl, especiallymethyl- ethyl- or i-propylsulfanyl; C₁₋₆alkylsulfinyl, especiallymethyl- ethyl- or i-propylsulfinyl; C₃₋₇heterocycloalkyl, especiallypiperidinyl most especially piperidin-3-yl such as1-methylpiperidin-3-yl or dithianyl especially [1,3]dithian-2-yl;C₆₋₁₂arylselenenyl, especially phenylselenenyl; C₆₋₁₂arylsulfanyl,especially phenylsulfanyl or pentafluorophenylsulfanyl; monocyclicC₁₋₉heteroaromaticsulfanyl, especially tetrazol-5-ylsulfanyl mostespecially 1-methyl-1H-terazol-5-ylsulfanyl or imidazolylsulfanylespecially imidazol-2-ylsulfanyl most especially1-methyl-1H-imidazol-2-ylsulfanyl; monocyclic C₁₋₉heteroaromatic,especially pyridinyl most especially pyridin-3-yl, 1-methylpyridinium orpyrazinyl especially pyrazin-2-yl; or a C₆₋₁₂arylC₁₋₃alkyl, especiallybenzyl group.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) and R^(z) is each a hydrogen atom.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) is a hydrogen atom and R^(z) is a halogen atom,especially a fluorine, chlorine, bromine or iodine atom, most especiallya chlorine or bromine atom, or R^(z) is a group -L¹(Alk¹)_(n)R³ as justdescribed.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) and R^(y) is each a hydrogen atom and R^(z) is ahalogen atom, especially a fluorine, chlorine, bromine or iodine atom,most especially a chlorine or bromine atom, or R^(z) is a group -L¹(Alk¹)_(n)R³ as just described.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) is a hydrogen atom and R^(y) is an optionallysubstituted alkyl group as just described for generally preferred alkylgroups.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) and R^(z) is each a hydrogen atom and R^(y) is anoptionally substituted alkyl group as just described.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) is a hydrogen atom, R^(z) is a halogen atom,especially a fluorine, chlorine, bromine or iodine atom, most especiallya chlorine or bromine atom or R^(z) is a group -L¹(Alk¹)_(n)R³,especially a group as just particularly described, and R^(y) is anoptionally substituted alkyl group as just described for generallypreferred alkyl groups.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) is a hydrogen atom and R^(y) and R^(z) is each anoptionally substituted alkyl group as just described for generallypreferred alkyl groups.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) and R^(y) is each an optionally substituted alkylgroup as just described for generally preferred alkyl groups.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) and R^(y) is each an optionally substituted alkylgroup as just described for generally preferred alkyl groups and R^(z)is a hydrogen atom.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) and R^(y) is each an optionally substituted alkylgroup as just described for generally preferred alkyl groups and R^(z)is a halogen atom, especially a fluorine, chlorine, bromine or iodineatom, most especially a chlorine or bromine atom, or R^(z) is a group-L¹ (Alk¹)_(n)R³ as just described.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x), R^(y) and R^(z) is each an optionally substitutedalkyl group as just described for generally preferred alkyl groups.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) and R^(y) are joined to form an optionallysubstituted spiro linked cycloaliphatic group particularly aC₃₋₁₀cycloaliphatic group, most particularly a C₃₋₈cycloalkyl group,especially an optionally substituted cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl group, or a C₃₋₈cycloalkenyl group, especiallyan optionally substituted cyclopentenyl, cyclohexenyl, cycloheptenyl orcyclooctenyl group group. Particularly preferred optional substituentswhich may be present on such spiro linked cycloaliphatic groups includehalogen atoms, especially fluorine or chlorine atoms, C₁₋₆alkyl groups,especially methyl, ethyl, propyl or i-propyl, C₁₋₆alkoxy groups,especially methoxy or ethoxy, haloC₁₋₆alkoxy groups, especially —OCF₃,—CN, —CO₂CH₃, —NO₂ and substituted amino (—N(R¹¹)₂), especially —NHCH₃and —N(CH₃)₂ groups. In a preferred group of compounds of this classR^(z) is a hydrogen atom. In another preferred group of compounds ofthis class R^(z) is an alkyl group as just described. In a furtherpreferred group of compounds of this class R^(z) is a halogen atom,especially a fluorine, chlorine, bromine or iodine atom, most especiallya chlorine or bromine atom, particularly a bromine atom. In a stillfurther preferred group of compounds of this class R^(z) is a group-L¹(Alk¹)_(n)R³ as just described.

In another preferred class of compounds of formulae (1), (2a), (2b),(2c) and (2d) R^(x) and R^(y) are joined to form an optionallysubstituted spiro linked heterocycloaliphatic group, particularly anoptionally substituted C₃₋₁₀heterocycloaliphatic group, mostparticularly an optionally substituted C₃₋₇heterocycloalkyl group,especially an optionally substituted C₃₋₇heterocycloalkyl groupcontaining one or two —O—, —S—, —S(O)—, —S(O)₂—, —NH— or —C(O)—heteroatoms or heteroatom-containing groups. Especially preferredoptionally substituted heterocycloaliphatic groups include optionallysubstituted 5- and 6-membered heterocycloalkyl groups containing oneheteroatom or heteroatom-containing group as just described, especiallyoptionally substituted pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydrothiophene-1-oxide,tetrahydrothiophene-1,1-dioxide, piperidinyl, tetrahydropyranyl,tetrahydrothiopyranyl tetra-hydrothiopyran-1-oxide ortetrahydrothiopyran-1,1-dioxide groups.

Particularly preferred optional substituents which may be present onsuch spiro linked heterocycloaliphatic groups include halogen atoms,especially fluorine or chlorine atoms, C₁₋₆alkyl groups, especiallymethyl, ethyl, propyl or i-propyl, C₁₋₆alkoxy groups, especially methoxyor ethoxy, haloC₁₋₆alkoxy groups, especially —OCF₃, —CN, —CO₂CH₃, —NO₂and substituted amino (—N(R¹¹)₂), especially —NHCH₃ and —N(CH₃)₂ groups.In addition when the spiro linked heterocycloaliphatic group contains anitrogen atom this may be substituted by a group -(L⁶)_(p)(Alk⁵)_(q)R¹²where L⁶ is preferably —C(O)— or —S(O)₂—, Alk⁵ is preferably anoptionally substituted C₁₋₆alkylene chain, especially a —CH₂—, —(CH₂)₂—or —CH(CH₃)CH₂— chain or an optionally substituted heteroC₁₋₆alkylenechain, especially —CH₂L⁵-, —CH₂CH₂L⁵-, -L⁵CH₂— or -L⁵CH₂CH₂ chain whereL⁵ is an —O— or —S— atom or —NH or —N(CH₃)— group and R¹² is a hydrogenatom or an optionally substituted phenyl ring where preferred optionalsubstituents include those atoms and groups as defined hereinbefore forR¹⁶ in relation to formula (2b). In one preferred group of compounds ofthis class R^(z) is a hydrogen atom. In another preferred group ofcompounds of this class R^(z) is an alkyl group as just described. In afurther preferred group of compounds of this class R^(z) is a halogenatom, especially a fluorine, chlorine, bromine or iodine atom, mostespecially a chlorine or bromine atom. In a still further preferredgroup of compounds of this class R^(z) is a group -L¹ (Alk¹)_(n)R³ asjust described.

Particularly useful compounds of the invention include:

-   (2S)-2-[(3-Oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(3-Oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(2,7)naphthyridin-1-yloxy]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3-oxo-7-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-{(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino}-3-(2,6-dimethoxy[1,1′-biphenyl]4-yl)propanoic    acid-   (2S)-2-[(3-Oxospiro[3.6]dec-1-en-1-yl)amino]3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3-oxospiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3    ,5-dichloroisonicotinoyl)amino]phenyl}propanoic acid-   (2S)-2-{[4,4-Dimethyl-2-(phenylselenenyl)-3-oxo-1-cyclobutenyl]amino}-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-7-methoxy-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-{(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino}-3-{4-[(3-methyl[2.7]naphthyridin-1-yl)oxy]phenyl}propanoic    acid-   (2S)-2-{[2-(Phenylsulfanyl)-4,4-dimethyl-3-oxo-1-cyclobutenyl]-amino}-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Chloro-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-pyridin-3-yl    -spiro[3.5]non-1-en-1-ylamino)-propanoic acid-   (2S)-2-[(2-Iodo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoic    acid-   (2S)-2-[(2-Chloro-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoic    acid-   (2S)-2-[(2-Chloro-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Chloro-3-oxo-spiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[4,4-Dimethyl-2-(1-methyl-1H-tetrazol-5-ylsulfanyl)-3-oxo-cyclobut-1-enylamino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3,7,7-trioxo-7λ⁶-thia-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Chloro-3-oxo-spiro[3.4]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3-oxo-spiro[3.4]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Methylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-(2-Fluoro-3-oxo-spiro[3.5]non-1-en-1-ylamino)3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Fluoro-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(4,4-Dimethyl-2-methylsulfanyl-3-oxo-cyclobut-1-enyl)amino]-3-{4-[(3,5-dicloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Isopropylsulfanyl-4,4-dimethyl-3-oxo-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Isopropylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Isopropylsulfanyl-4,4-dimethyl-3-oxo-cyclobut-1-enyl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoic    acid-   (2S)-2-[(2-Isopropylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoic    acid-   (2S)-2-[(2-Isopropylsulfanyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoic    acid-   (2S)-2-[(2-Bromo-3-oxo-spiro[3.4]octa-1,6-dien-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(4,4-Dimethyl-3-oxo-2-pentafluorophenylsulfanyl-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(4,4-Dimethyl-3-oxo-2-pyrazin-2-yl-cyclobut-1-enyl)amino]-3-{4[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(7-Acetyl-2-bromo-3-oxo-7-aza-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-{[2-(Isopropylsulfanyl)-3-oxo-7-oxaspiro[3.5]non-1-en-yl)]amino}-3-(2,6-dimethoxy[1,1′-biphenyl]4-yl)propanoic    acid-   (2S)-2-[(2-Cyclohexyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-methyl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoic    acid-   (2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-propyl-spiro[3.5]non-1-en-1-ylamino)propanoic    acid-   (2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-methyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1-ylamino)propanoic    acid-   (2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-propyl-7-oxa-spiro[3.5]non-1-en-1-ylamino)propanoic    acid-   (2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-[1,3]dithian-2-yl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoic    acid-   (2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-ethyl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoic    acid-   (2S)-3-{4-[(3,5-Dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}-2-(3-oxo    -spiro[3.5]non-1-en-1-ylamino)propanoic acid-   (2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoic    acid-   (2S)-2-(2-Chloro-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoic    acid-   (2S)-3-{4-[(3,5-Dichloro-1-oxy-pyridine-4-carbonyl)-amino]-phenyl}-2-(2-methanesulfinyl-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)-propanoic    acid-   (2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4-(3-methyl-[2,7]naphthyridin-1-ylamino)phenyl]propanoic    acid-   (2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoic    acid-   (2S)-2-(2-Bromo-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)-3-[4-(3-methyl-[2,7]naphthyridin-1-yloxy)phenyl]propanoic    acid-   (2S)-2-[(2-Bromo-3-oxo-spiro[3.4]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid    and the salts, solvates, hydrates, N-oxides and carboxylic acid    esters thereof.

Particularly useful carboxylic acid esters thereof include the methyl,ethyl, propy, i-propyl and t-butyl esters.

Most especially useful compounds of the invention include:

-   (2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3-oxo-7-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3-oxospiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-{(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino}-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoic    acid-   (2S)-2-{[2-(Phenylsulfanyl)-4,4-dimethyl-3-oxo-1-cyclobutenyl]-amino}-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Chloro-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-pyridin-3-yl-spiro[3.5]non-1-en-1-ylamino)propanoic    acid-   (2S)-2-[(2-Iodo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoic    acid-   (2S)-2-[(2-Chloro-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoic    acid-   (2S)-2-[(2-Chloro-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Chloro-3-oxo-spiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3,7,7-trioxo-7λ⁶-thia-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Chloro-3-oxo-spiro[3.4]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Bromo-3-oxo-spiro[3.4]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Methylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-(2-Fluoro-3-oxo-spiro[3.5]non-1-en-1-ylamino)3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Fluoro-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(4,4-Dimethyl-2-methylsulfanyl-3-oxo-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-isopropylsulfanyl-4,4-dimethyl-3-oxo-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Isopropylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(2-Isopropylsulfanyl-4,4-dimethyl-3-oxo-cyclobut-1-enyl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoic    acid-   (2S)-2-[(2-Isopropylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoic    acid-   (2S)-2-[(2-Isopropylsulfanyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoic    acid-   (2S)-2-[(2-Bromo-3-oxo-spiro[3.4]octa-1,6-dien-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-2-[(7-Acetyl-2-bromo-3-oxo-7-aza-spiro[3.5]non-1-en-1-yl    )amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic acid-   (2S)-2-[(2-Cyclohexyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic    acid-   (2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-methyl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoic    acid-   (2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-propyl-spiro[3.5]non-1-en-1-ylamino)propanoic    acid-   (2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-[1,3]dithian-2-yl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoic    acid-   (2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoic    acid-   (2S)-2-(2-Chloro-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoic    acid    and the salts, solvates, hydrates, N-oxides and carboxylic acid    esters thereof.

Particularly useful carboxylic acid esters thereof include the methyl,ethyl, propy, i-propyl and t-butyl esters.

Particularly useful ester prodrugs of compounds of the inventioninclude:

-   Ethyl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   Isopropyl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   t-Butyl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   1-Methyl-piperidin-4-yl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   Phenyl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   Cyclopentyl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   2-Imidazol-1-yl-ethyl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   Neopentyl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   Tetrahydro-furan-3-yl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   Pyridin-4-ylmethyl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   Tetrahydropyran-4-yl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]-phenyl}propanoate-   1-Methyl-pyrrolidin-3-yl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   2,3-Dihydroxypropyl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate-   Tetrahydrofuran-2-ylmethyl    (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate    and the salts, solvates, hydrates and N-oxides thereof.

Compounds according to the invention are potent and selective inhibitorsof α4 integrins. The ability of the compounds to act in this way may besimply determined by employing tests such as those described in theExamples hereinafter.

The compounds are of use in modulating cell adhesion and in particularare of use in the prophylaxis and treatment of diseases or disordersincluding inflammation in which the extravasation of leukocytes plays arole and the invention extends to such a use and to the use of thecompounds for the manufacture of a medicament for treating such diseasesor disorders,

Diseases or disorders of this type include inflammatory arthritis suchas rheumatoid arthritis vasculitis or polydermatomyositis, multiplesclerosis, allograft rejection, diabetes, inflammatory dermatoses suchas psoriasis or dermatitis, asthma and inflammatory bowel disease.

For the prophylaxis or treatment of disease the compounds according tothe invention may be administered as pharmaceutical compositions, andaccording to a further aspect of the invention we provide apharmaceutical composition which comprises a compound of formula (1)together with one or more pharmaceutically acceptable carriers,excipients or diluents.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical or rectaladministration, or a form suitable for administration by inhalation orinsufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles and preservatives. Thepreparations may also contain buffer salts, flavouring, colouring andsweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds for formula (1) may be formulated for parenteraladministration by injection e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoule or multi dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds offormula (1) may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsfor use according to the present invention are conveniently delivered inthe form of an aerosol spray presentation for pressurised packs or anebuliser, with the use of suitable propellant, e.g.dichlorodifluoromethane, trichloro-fluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

The quantity of a compound of the invention required for the prophylaxisor treatment of a particular condition will vary depending on thecompound chosen, and the condition of the patient to be treated. Ingeneral, however, daily dosages may range from around 10 ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccaladministration, from around 10 ng/kg to 50 mg/kg body weight forparenteral administration and around 0.05 mg to around 1000 mg e.g.around 0.5 mg to around 1000 mg for nasal administration oradministration by inhalation or insufflation.

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process description, the symbols Ar¹, Ar²,Alk, R¹, R², R³, L¹, L², Alk¹, R^(x), R^(y), R^(z) and n when used inthe formulae depicted are to be understood to represent those groupsdescribed above in relation to formula (1) unless otherwise indicated.In the reactions described below, it may be necessary to protectreactive functional groups, for example hydroxy, amino, thio or carboxygroups, where these are desired in the final product, to avoid theirunwanted participation in the reactions. Conventional protecting groupsmay be used in accordance with standard practice [see, for example,Green, T. W. in “Protective Groups in Organic Synthesis”, John Wiley andSons, 1999]. In some instances, deprotection may be the final step inthe synthesis of a compound of formula (1) and the processes accordingto the invention described hereinafter are to be understood to extend tosuch removal of protecting groups. For convenience the processesdescribed below all refer to a preparation of a compound of formula (1)but clearly the description applies equally to the preparation ofcompounds of formula (2).

Thus according to a further aspect of the invention, a compound offormula (1) in which R is a —CO₂H group may be obtained by hydrolysis ofan ester of formula (1a):

where Alk represents a group

[where Alk⁷ is an alkyl group for example a C₁₋₆alkyl group].

The hydrolysis may be performed using either an acid or a base dependingon the nature of Alk⁷, for example an organic acid such astrifluoroacetic acid or an inorganic base such as lithium, sodium orpotassium hydroxide optionally in an aqueous organic solvent such as anamide e.g. a substituted amide such as dimethylformamide, an ether e.g.a cyclic ether such as tetrahydrofuran or dioxane or an alcohol e.g.methanol at a temperature from ambient to the reflux temperature. Wheredesired, mixtures of such solvents may be used.

According to a further aspect of the invention a compound of formula (1)may be prepared by condensation of a compound of formula (3):

where compounds of formula (3) exist as two tautomeric isomers, (3a) and(3b) in solution with an amine of formula R¹R²NH, an alcohol of formulaR¹OH or a thiol of formula R¹SH.

The reaction may be performed in an inert solvent or mixture ofsolvents, for example a hydrocarbon such as an aromatic hydrocarbon e.g.benzene or toluene and/or a halogenated hydrocarbon such as1,2-dichloroethane, or dichloromethane at a temperature from 0°C. to thereflux temperature. Where necessary, for example when a salt of an amineR¹R²NH is used, an organic base such as diisopropylethylamine can beadded.

Any carboxylic acid group present in the intermediate of formula (3) orthe amine R¹R²NH, alcohol R¹OH or thiol R¹SH may need to be protectedduring the displacement reaction, for example as an ethyl ester. Thedesired acid may then be obtained through subsequent hydrolysis, forexample as particularly described above and generally described below.

The displacement reaction may also be carried out on an intermediate offormula 4 (see below) under the conditions just described.

Where desired the displacement reaction may also be performed on anintermediate of formulae (3), R¹R²NH, R¹OH or R¹SH which is linked, forexample via its R, R¹ or R³ group, to a solid support, such as apolystyrene resin. After the reaction the desired compound of formula(1) may be displaced from the support by any convenient method,depending on the original linkage chosen.

Intermediates of formulae (3) R¹R²NH, R¹OH and R¹SH may be obtained fromsimpler, known compounds by one or more standard synthetic methodsemploying substitution, oxidation, reduction or cleavage reactions.Particular substitution approaches include conventional alkylation,arylation, heteroarylation, acylation, thioacylation, halogenation,sulphonylation, nitration, formylation and coupling procedures. It willbe appreciated that these methods may also be used to obtain or modifyother compounds of formulae (1) and (2a), (2b), (2c) and (2d) whereappropriate functional groups exist in these compounds.

Thus intermediates of formula (3) may be obtained by hydrolysis ofintermediates of formula (4):

where R^(a) represents a C₁₋₆alkyl group or a silyl group such as a^(t)butyidimethylsilyl group.

The hydrolysis may be performed using an acid, for example an inorganicacid such as hydrochloric acid in an organic solvent such as an ethere.g. diethylether, or an alcohol e.g. ethanol optionally in the presenceof added water at a temperature from about ambient to 80° C.

Intermediates of formula (4) may be obtained by the cycloaddition of anintermediate of formula (5):

with a ketene of formula (6):

preformed or generated in situ during the cycloaddition reaction from anacid chloride of formula (7):

The reaction may be performed in the presence of an organic base such asan amine e.g. triethylamine or N,N-diisopropylethylamine or a cyclicamine such as pyridine or N-methylmorpholine optionally in an organicsolvent such as an ether e.g. diethylether or diisopopylether.

Acid chlorides of formula (7) may be obtained from the correspondingacids by a convenient method of generating acid halides, for example byreaction with thionyl chloride or oxalyl chloride under such standardconditions as are well known in the art.

Compounds of formula (1a) in which R^(z) is for example a halogen atommay be obtained from compounds of formula (1a) in which R^(z) is ahydrogen atom by reaction with a halogen source such as bromine or ahalosuccinamide e.g. chloro or bromosuccinamide. The reaction may beperformed in a solvent such as an ether e.g. a cyclic ether such astetrahydrofuran at a temperature from about 0° to 30°. When bromine isused as halogen source the reaction may optionally be performed in thepresence of added base such as an amine e.g. triethylamine.

Further compounds of formula (1a) in which R^(z) is a group-L¹(Alk¹)_(n)(R³)_(v) in which L¹ is for example a Se, S, O or N(R⁸) maybe prepared by reaction of an intermediate of formulaHL¹(Alk¹)_(n)(R³)_(v) with a compound of formula (1a) in which R^(z) isa hydrogen atom. The reaction may be performed in an organic solventsuch as an ether e.g. a cyclic ether such as tetrahydrofuran at aroundroom temperature optionally in the presence of a base such as an aminee.g. triethylamine.

Intermediate compounds of formula (4) may also be obtained from squaricacid derivations by such well known methods in the art as those ofMacDougall, J. M. et al, J. Org. Chem, 64 5979-83 (1999); Hergueta, R.A., J. Org. Chem., 64, 5979-83, (1999); Heileman, M. J. et al, J. Am.Chem. Soc. 120, 3801-2, (1998); Yamamoto, Y. et al, J. Org. Chem, 62,1292-8 (1997); Zhag, D. et al, J. Org. Chem. 61, 2594-5 (1996); Petasis,N. A. et al, Synlett, 155-6 (1996); Petasis, N. A. et al, TetrahedronLeft., 36, 600-14, (1995); Turnbull, P. et al, J. Org. Chem 60, 644-9(1995); Yerxa, B. R. et al, Tetrahedron, 50, 6173-80 (1994); Ezcurra, J.E. et al, Tetrahedron Lett, 34, 6177-80, (1993); Ohno, M. et al,Tetrahedron Lett., 34, 4807-10, (1993); Yerxa, B. R. et al, TetrahedronLett. 33, 7811-14 (1992); Xu, S. L. et al, J. Org. Chem, 57, 326-8(1992) and Kravs, J. L. et al, Tetrahedron Lett. 28, 1765-8 (1987).

Further compounds of the invention and intermediates thereto may beprepared by alkylation, arylation or heteroarylation. For example,compounds containing a -L¹H or -L²H group (where L¹ and L² is each alinker atom or group) may be treated with a coupling agentR³(Alk¹)_(n)X¹ or Ar¹X¹ respectively in which X¹ is a leaving atom orgroup such as a halogen atom, e.g. a fluorine, bromine, iodine orchlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g.trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g.p-toluenesulphonyloxy group.

The reaction may be carried out in the presence of a base such as acarbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g.potassium t-butoxide, or a hydride, e.g. sodium hydride, or an organicamine e.g. triethylamine or N,N-diisopropylethylamine or a cyclic amine,such as N-methylmorpholine or pyridine, in a dipolar aprotic solventsuch as an amide, e.g. a substituted amide such as dimethylformamide oran ether, e.g. a cyclic ether such as tetrahydrofuran.

Compounds of formula Ar¹X¹ may be prepared from alcohols of formulaAr¹OH by reaction with a halogenating agent, for example a phosphorousoxyhalide such as phosphorous oxychloride at an elevated temperaturee.g. 110° C.

Intermediate alcohols of formula Ar¹OH in which, for example, Ar¹represents a 2,6-naphthyridine may be prepared by methods well known toa person skilled in the art, e.g. by the method of Sakamoto, T. et al[Chem. Pharm. Bull. 33, 626-633, (1985)].

Alternatively alkylating agents of formula Ar¹X¹ in which, for example,Ar¹ represents a 2,6-naphthyridine may be prepared by reaction of a2,6-naphthyridine N-oxide or N,N′-dioxide with a halogenating agent,e.g. a phosphorous oxyhalide such as phosphorous oxychloride to give a1-halo or 1,5-dihalo-2,6-napthyridine respectively. In the case of1,5-dihalo-2,6-napthyridines each halogen atom may be substitutedseparately by a reagent such as HL²Ar²AlkN(R²)H orHL³(Alk²)_(t)L⁴(R⁴)_(u) by the particular methods just described above.

2,6-Napthyridine N-oxides and N,N′-dioxides may be generated from thecorresponding 2,6-napthyridines by the general methods of synthesis ofN-oxides described below or they may be synthesised by the methods ofNumata, A. et al (Synthesis, 1999, 306-311).

Further alkylating agents of formula Ar¹X¹ in which, for example, Ar¹represents a 2,6-naphthyridine, may be prepared by the methods ofGiacomello G. et al [Tetrahedron Letters, 1117-1121 (1965)], Tan, R. andTaurins, A. [Tetrahedron Lett., 2737-2744, (1965)], Ames, D. E. andDodds, W. D. [J. Chem. Soc. Perkin 1, 705-710 (1972)] and Alhaique, F.et al [Tetrahedron Lett., 173-174 (1975)].

Intermediate alcohols of formula Ar¹OH in which Ar¹ represents anoptionally substituted 2,7-naphthyridin-1-yl group may be prepared bymethods well known to a person skilled in the art, e.g. by the method ofSakamoto, T. et al [Chem. Pharm. Bull. 33, 626-633, (1985)] or Baldwin,J, J. et al [J. Org. Chem, 43, 4878-4880, (1978)]. Thus for example themethod of Baldwin may be modified to allow the synthesis of intermediate3-substituted 2,7-naphthyridin-1-yl groups of formula Ar¹OH as depictedin Scheme 1.

Reaction of an optionally substituted 4-methyl-3-cyano pyridine offormula (8) with a N,N-dimethylformamide di-C₁₋₆alkyl acetal, e.g.N,N-dimethyl-formamide diethyl acetal, in a dipolar solvent such as anamide e.g. a substituted amide such as dimethylformamide at an elevatedtemperature e.g. 140-150° gives a compound of formula (9) or (10) or amixture thereof depending on the nature of the group R¹⁶.

Compounds of formula (9) or (10) may be cyclised to 3-substituted2,7-naphthyridin-1-yl alcohol of formula (11) by treatment with an acide.g. an inorganic acid such as hydrochloric acid or hydrobromic acid oran acidic gas such as hydrogen chloride gas in an organic solvent e.g.an organic acid such as acetic acid optionally in the presence of waterat a temperature from about ambient to 50° C.

Alternatively alkylating agents of formula Ar¹X¹ in which Ar¹ representsan optionally substituted 2,7-naphthyridin-yl group may be prepared byreaction of a 2,7-naphthyridine N-oxide or N,N′-dioxide with ahalogenating agent, e.g. a phosphorous oxyhalide such as phosphorousoxychloride to give a 1-halo or 1,6-dihalo-and/or-1,8-dihalo-2,7-napthyridine respectively. In the case of1,6-dihalo- and/or 1,8-dialo-2,6-napthyridines each halogen atom may besubstituted separately by a reagent such as HL²Ar²AlkN(R²)H orHL³(Alk²)_(t)L⁴(R⁴)_(u) by the particular methods just described above.

2,7-Napthyridine N-oxides and N,N′-dioxides may be generated from thecorresponding 2,7-napthyridines by the general methods of synthesis ofN-oxides described below or they may be synthesised by the methods ofNumata, A. et al (Synthesis, 1999, 306-311).

Further alkylating agents of formula Ar¹X¹ in which, for example, Ar¹represents a 2,7-naphthyridin-1-yl, may be prepared by the methods ofWenkert E. et al J. Am. Chem. Soc. 89, 6741-5 (1967), and Aust. J. Chem.433 (1972), and Sheffield D. J. J. Chem. Soc. Perkin. Trans I, 2506(1972).

Intermediate alcohols of formula Ar¹OH in which Ar¹ represents a3-substituted isoquinolin-1-yl group may be prepared by methods wellknown to a person skilled in the art, e.g. by the methods of Wu M.-J. etal Tetrahedron, 55, 13193-200 (1999), Hiebl J. et al Tetrahedron Left.40, 7935-8 (1999), Nagarajan A. et al Indian J. Chem., Sect. B, 28B,67-78 (1989), Brun E. M. et al Synlett, 7, 1088-90 (1999) and Brun, E.M. et al Synthesis, 273-280 (2000).

Further alkylating agents of formula Ar¹X¹ in which, for example, Ar¹represents a isoquinolin-1-yl group, may be prepared by the methods ofFalk H. et al Monatsch. Chem. 25, 325-33 (1994), and Deady, L. W. et alAust. J. Chem 42, 1029-34 (1989).

In a further example intermediates of formula R¹R²NH may be obtained byreaction of a compound of formula Ar¹L²H with a compound of formulaX¹Ar²AlkN(R²)H under the reaction conditions just described

Compounds of formula Ar¹L²H in which, for example Ar¹ represents a2,6-naphthyridine and L² is a —N(R⁸)— group, may be prepared fromsubstituted 4-cyano-3-cyanomethylpyridines by the methods of Alhaique,F. et al (ibid and Gazz. Chim. Ital. 1975, 105, 1001-1009) or from3-fomylpyridines by the methods of Molina, P. at al (Tetrahedron 1992,48, 4601-4616).

Compounds of formula Ar¹L²H in which, for example Ar¹ represents a2,7-naphthyridin-1-yl group and L² is a —N(R⁸)— group, may be preparedfrom substituted 4-formylpyridines by the methods of Molina, P. et alTetrahedron, 48, 4601-4616, (1992), or by the methods described in U.S.Pat. No. 3,938,367.

Compounds of formula Ar¹L²H in which, for example Ar¹ represents a3-substituted isoquinolin-1-yl group and L² is a —N(R⁸)— group, may beprepared by the methods of Bordner, J. et al J. Med. Chem. 31, 1036-9(1988), Tovar J. D. et al J. Org. Chem., 64, 6499-6504 (1999), Karser E.M. et al Synthesis, 11, 805-6 (1974), and Molino, P et al J. Chem. Soc.Perkin Trans. 1,1727-31 (1990).

In another example, compounds containing a -L¹H or -L²H or group asdefined above may be functionalised by acylation or thioacylation, forexample by reaction with one of the alkylating agents just described butin which X¹ is replaced by a —C(O)X², —C(S)X², —N(R⁸)COX² or—N(R⁸)C(S)X² group in which X² is a leaving atom or group as describedfor X¹. The reaction may be performed in the presence of a base, such asa hydride, e.g. sodium hydride or an amine, e.g. triethylamine orN-methylmorpholine, in a solvent such as a halogenated hydrocarbon, e.g.dichloromethane or carbon tetrachloride or an amide, e.g.dimethylformamide, at for example ambient temperature. Alternatively,the acylation may be carried out under the same conditions with an acid(for example one of the alkylating agents described above in which X¹ isreplaced by a —CO₂H group) in the presence of a condensing agent, forexample a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideor N,N′-dicyclohexylcarbodiimide, advantageously in the presence of acatalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as1-hydroxybenzotriazole. Alternatively the acid may be reacted with achloroformate, for example ethylchloroformate, prior to the desiredacylation reaction.

In a further example compounds may be obtained by sulphonylation of acompound containing an —OH group by reaction with one of the abovealkylating agents but in which X¹ is replaced by a —S(O)Hal or —SO₂Halgroup [in which Hal is a halogen atom such as chlorine atom] in thepresence of a base, for example an inorganic base such as sodium hydridein a solvent such as an amide, e.g. a substituted amide such asdimethylformamide at for example ambient temperature.

In another example, compounds containing a -L¹H or -L²H group as definedabove may be coupled with one of the alkylation agents just describedbut in which X¹ is replaced by an —OH group in a solvent such astetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphineand an activator such as diethyl, diisopropyl- ordimethylazodicarboxylate.

In a further example, ester groups —CO₂R⁵, —CO₂R¹¹ or —CO₂Alk⁷ in thecompounds may be converted to the corresponding acid [—CO₂H] by acid- orbase-catalysed hydrolysis depending on the nature of the groups R⁵, R¹¹or Alk⁷. Acid- or base-catalysed hydrolysis may be achieved for exampleby treatment with an organic or inorganic acid, e.g. trifluoroaceticacid in an aqueous solvent or a mineral acid such as hydrochloric acidin a solvent such as dioxan or an alkali metal hydroxide, e.g. lithiumhydroxide in an aqueous alcohol, e.g. aqueous methanol.

In a further example, —OR⁵ or —OR¹⁴ groups [where R⁵ or R¹⁴ eachrepresents an alkyl group such as methyl group] in compounds of formula(1) may be cleaved to the corresponding alcohol —OH by reaction withboron tribromide in a solvent such as a halogenated hydrocarbon, e.g.dichloromethane at a low temperature, e.g. around −78° C.

Alcohol [—OH] groups may also be obtained by hydrogenation of acorresponding —OCH₂R¹⁴ group (where R¹⁴ is an aryl group) using a metalcatalyst, for example palladium on a support such as carbon in a solventsuch as ethanol in the presence of ammonium formate, cyclohexadiene orhydrogen, from around ambient to the reflux temperature. In anotherexample, —OH groups may be generated from the corresponding ester[CO₂Alk⁷ or CO₂R⁵] or aldehyde [—CHO] by reduction, using for example acomplex metal hydride such as lithium aluminium hydride or sodiumborohydride in a solvent such as methanol.

In another example, alcohol —OH groups in the compounds may be convertedto a corresponding —OR⁵ or —OR¹⁴ group by coupling with a reagent R⁵OHor R¹⁴OH in a solvent such as tetrahydrofuran in the presence of aphosphine, e.g. triphenylphosphine and an activator such as diethyl-,diisopropyl-, or dimethylazodicarboxylate.

Aminosulphonylamino [—NHSO₂NHR³ or —NHSO₂NHAr¹] groups in the compoundsmay be obtained, in another example, by reaction of a correspondingamine [—NH₂] with a sulphamide R³NHSO₂NH₂ or Ar¹NHSO₂NH₂ in the presenceof an organic base such as pyridine at an elevated temperature, e.g. thereflux temperature.

In another example compounds containing a —NHCSAr¹, —CSNHAr¹, —NHCSR³ or—CSNHR³ may be prepared by treating a corresponding compound containinga —NHCOAr¹, —CONHAr¹, —NHCOR³ or —CONHR³ group with a thiation reagent,such as Lawesson's Reagent, in an anhydrous solvent, for example acyclic ether such as tetrahydrofuran, at an elevated temperature such asthe reflux temperature.

In a further example amine (—NH₂) groups may be alkylated using areductive alkylation process employing an aldehyde and a borohydride,for example sodium triacetoxyborohyride or sodium cyanoborohydride, in asolvent such as a halogenated hydrocarbon, e.g. dichloromethane, aketone such as acetone, or an alcohol, e.g. ethanol, where necessary inthe presence of an acid such as acetic acid at around ambienttemperature.

In a further example, amine [—NH₂] groups in compounds of formula (1)may be obtained by hydrolysis from a corresponding imide by reactionwith hydrazine in a solvent such as an alcohol, e.g. ethanol at ambienttemperature.

In another example, a nitro [—NO₂] group may be reduced to an amine[—NH₂], for example by catalytic hydrogenation using for examplehydrogen in the presence of a metal catalyst, for example palladium on asupport such as carbon in a solvent such as an ether, e.g.tetrahydrofuran or an alcohol e.g. methanol, or by chemical reductionusing for example a metal, e.g. tin or iron, in the presence of an acidsuch as hydrochloric acid.

Aromatic halogen substituents in the compounds may be subjected tohalogen-metal exchange with a base, for example a lithium base such asn-butyl or t-butyl lithium, optionally at a low temperature, e.g. around−78° C., in a solvent such as tetrahydrofuran and then quenched with anelectrophile to introduce a desired substituent, for example, a formylgroup may be introduced by using dimethylformamide as the electrophile;a thiomethyl group may be introduced by using dimethyidisulphide as theelectrophile.

In another example, sulphur atoms in the compounds, for example whenpresent in a linker group L¹ or L² may be oxidised to the correspondingsulphoxide or sulphone using an oxidising agent such as a peroxy acid,e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as ahalogenated hydrocarbon, e.g. dichloromethane, at around ambienttemperature.

In another example compounds of formula Ar¹X¹ (where X¹ is a halogenatom such as a chlorine, bromine or iodine atom) may be converted tosuch compounds as Ar¹CO₂R²⁰ (in which R²⁰ is an optionally substitutedalkyl, aryl or heteroaryl group), Ar¹CHO, Ar¹CHCHR²⁰, Ar¹CCR²⁰,Ar¹N(R²⁰)H, Ar¹N(R²⁰)₂, for use in the synthesis of for examplecompounds of formula Ar¹L²Ar²AlkN(R²)H, using such well know andcommonly used palladium mediated reaction conditions as are to be foundin the general reference texts Rodd's Chemistry of Carbon Compounds,Volumes 1-15 and Supplementals (Elsevier Science Publishers, 1989),Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-19 (JohnWiley and Sons, 1999), Comprehensive Heterocyclic Chemistry, Ed.Katritzky et al, Volumes 1-8, 1984 and Volumes 1-11, 1994 (Pergamon),Comprehensive Organic Functional Group Transformations, Ed. Katritzky etal, Volumes 1-7, 1995 (Pergamon), Comprehensive Organic Synthesis, Ed.Trost and Flemming, Volumes 1-9, (Pergamon, 1991), Encyclopedia ofReagents for Organic Synthesis, Ed. Paquette, Volumes 1-8 (John Wileyand Sons, 1995), Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989) and March's Advanced Organic Chemistry (JohnWiley and Sons, 1992).

N-oxides of compounds of formula (1) may be prepared for example byoxidation of the corresponding nitrogen base using an oxidising agentsuch as hydrogen peroxide in the presence of an acid such as aceticacid, at an elevated temperature, for example around 70° C. to 80° C.,or alternatively by reaction with a peracid such as peracetic acid in asolvent, e.g. dichloromethane, at ambient temperature.

Salts of compounds of formula (1) may be prepared by reaction of acompound of formula (1) with an appropriate base in a suitable solventor mixture of solvents e.g. an organic solvent such as an ether e.g.diethylether, or an alcohol, e.g. ethanol using conventional procedures.

Where it is desired to obtain a particular enantiomer of a compound offormula (1) this may be produced from a corresponding mixture ofenantiomers using any suitable conventional procedure for resolvingenantiomers.

Thus for example diastereomeric derivatives, e.g. salts, may be producedby reaction of a mixture of enantiomers of formula (1) e.g. a racemate,and an appropriate chiral compound, e.g. a chiral base. Thediastereomers may then be separated by any convenient means, for exampleby crystallisation and the desired enantiomer recovered, e.g. bytreatment with an acid in the instance where the diastereomer is a salt.

In another resolution process a racemate of formula (1) may be separatedusing chiral High Performance Liquid Chromatography. Alternatively, ifdesired a particular enantiomer may be obtained by using an appropriatechiral intermediate in one of the processes described above.Alternatively, a particular enantiomer may be obtained by performing anenantiomer specific enzymatic biotransformation e.g. an ester hydrolysisusing an esterase and then purifying only the enantiomerically purehydrolysed acid from the unreacted ester antipode.

Chromatography, recrystallisation and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular geometric isomer of the invention.

The following Examples illustrate the invention. All temperatures are in° C.

The following abbreviations are used:

-   NMM—N-methylmorpholine;-   MeOH—methanol;-   DCM—dichloromethane;-   DIPEA—diisopropylethylamine;-   Pyr—pyridine;-   DMSO—dimethylsulphoxide;-   Et₂O—diethylether;-   THF—tetrahydrofuran,-   FMOC—9-fluorenylmethoxycarbonyl;-   DBU—1,8-Diazabicyclo[5,4-0]undec-7-ene;-   DMAP—4-(dimethylamino)pyridine.-   HOBT—1-hydroxybenzotriazole-   EtOAc—ethyl acetate;-   BOC—butoxycarbonyl;-   AcOH—acetic acid;-   EtOH—ethanol;-   Ar—aryl;-   iPr—isopropyl;-   Me—methyl;-   DMF—N,N-dimethylformamide;

All NMR's were obtained either at 300 MHz or 400 MHz.

All Intermediates and Examples were named with the aid of BeilsteinAutonom (available from MDL Information Systems GmbH,Therdor-Heuss-Allee 108D 60486, Frankfurt, Germany) or were given namesthat seemed consistent, with the exception that propanoates were namedby the IUPAC name rather than the trivial name (propionate) andisonicotinoyl (trivial name) is used in place of pyridine-4-carbonyl.

Intermediate 1 (+/−) 3-Ethoxy-4-methyl-4-propyl-2-cyclobuten-1-one

The title compound was prepared using a modification of the method ofWasserman, H. H. et al [J. Org. Chem, 38, 1451-1455, (1973)]; to asolution of 2-methyl pentanoyl chloride (3.91 ml) and ethyl ethynylether(5 g, 40% solution in hexanes, 28.6 mmol) in ET₂O (35 ml) at roomtemperature was added triethylamine (9.9 ml), with stirring. Thereaction was warmed to 50° and stirred for 72 h prior to cooling andfiltration. The filtrate was concentrated in vacuo and the residual oilchromatographed (SiO₂; hexanes 80:EtOAc 20) to give the title compoundas a colourless oil (3.71 g, 17.9 mmol, 77%). δH (CDCl₃, 300K), 4.84(1H, s), 4.24-3.98 (2H, m), 2.04 (3H, s), 1.56-1.43 (4H, m), 1.30-1.26(3H, m), 0.91 (3H, t, J 7.3 Hz). m/z (ES⁺, 70V) 178.1 (MH⁺).

Intermediate 2 (+/−) 3-Hydroxy-4-methyl-4-propyl-2-cyclobuten-1-one

Intermediate 1 (1 g, 59.5 mmol) and conc. hydrochloric acid (2 ml) werestirred vigorously at room temperature for 48 h. The resulting slurrywas filtered and the residue washed with water (3×10 ml) and dried undervacuum to give the title compound as an off-white powder (620 mg, 44.2mmol, 74%). δH (CDCl₃, 300K) 3.79 (2H, s), 1.59-1.53 (2H, m), 1.41-1.27(2H, m), 1.18 (3H, s), 0.85 (3H, t, J 7.3 Hz). m/z (ES⁺, 70V) 140.9(MH⁺).

Intermediate 3 3-Ethoxy-4,4-dipropyl-2-cyclobuten-1-one

The title compound was prepared using a modification of the method ofWasserman, H. H. et al, [J. Org. Chem, 38, 1451-1455, (1973)];triethylamine (29 ml) was added dropwise at room temperature to awell-stirred solution of di-n-propylacetyl chloride (13.9 g, 85.8 mmol)and ethyl ethynylether (15 g, 40% solution in hexanes, 85.7 mmol) intoluene (120 ml. The reaction was warmed to 60° and stirred for 48 hprior to cooling and filtration. The filtrate was concentrated in vacuoand the residual oil chromatographed (SiO₂; hexanes 80:EtOAc 20) to givethe title compound as a brown oil (11.2 g, 57.1 mmol, 67%). δH (CDCl₃,300K) 5.02 (1H, s), 4.32 (2H, q, J 7.1 Hz), 1.69-1.61 (4H, m), 1.45-1.40(4H, m), 1.02 (6H, t, J 7.3 Hz). m/z (ES⁺, 70V) 197.1 (MH⁺).

Intermediate 4 3-Hydroxy-4,4-dipropyl-2-cyclobuten-1-one

Intermediate 3 (10.2 mmol) and 6M hydrochloric acid (10 ml) were stirredvigorously at 65° for 72 h. The resulting slurry was diluted with DCM(30 ml) and distilled water (30 ml) and extracted with DCM (3×10 ml).The combined extracts were dried (MgSO₄), filtered and concentrated invacuo to give the title compound as a pale yellow oil, whichcrystallised on standing (1.49 g, 8.87 mmol, 87%).

Intermediate 5 3-Ethoxy-2-hexyl-4,4-dimethyl-2-cyclobuten-1-one

The title compound was prepared using a modification of the method ofWasserman, H. H. et al, [J. Org. Chem, 38, 1451-1455, (1973)];triethylamine (22 ml) was added dropwise at room temperature to awell-stirred solution of isobutyryl chloride (7.3 ml, 69 mmol) and1-ethoxy-1-octyne [prepared according to the method of Kocienski, P. etal. Tetrahedron Lett. 1833, 30, (1989)] (6.5 g, 63 mmol) in diethylether(100 ml). The reaction was warmed to 35° and stirred for 96 h prior tocooling and filtration. The filtrate was concentrated in vacuo and theresidual oil chromatographed (SiO₂; hexanes 80:EtOAc 20) to give thetitle compound as a brown oil (8.6 g, 38 mmol, 61%). δH (CDCl₃, 300K)4.34 (2H, d, J 7.1 Hz), 2.05 (2H, dd, J 5.6 Hz, 7.3 Hz), 1.44 (3H, t, J7.1 Hz), 1.27-1.12 (8H, m), 1.23 (6H, s), 0.89 (3H, t, J 2.7 Hz). m/z(ES⁺, 70V) 225.0 (MH⁺).

Intermediate 6 2-Hexyl-3-hydroxy-4,4-dimethyl-2-cyclobuten-1-one

Intermediate 5 (7.6 g, 34.0 mmol) and 6M hydrochloric acid (10 ml) werestirred vigorously at 100° for 18 h. The resulting slurry was dilutedwith DCM (30 ml) and distilled water (30 ml) and extracted with DCM(3×10 ml). The combined extracts were dried (MgSO₄), filtered andconcentrated in vacuo. The residue was triturated with hexanes andfiltered to give the title compound as an off-white powder (6.5 g, 33.0mmol, 98%). δH (CDCl₃, 300K) 2.01 (2H, t, J 7.0 Hz), 1.49-1.44 (2H, m),1.34-1.19 (14H, m), 0.89-0.84 (3H, m). m/z (ES⁺, 70V) 197.0 (MH⁺).

Intermediate 7 (+/−) 4-Benzyl-3-ethoxy-4-methyl-2-cyclobuten-1-one

The title compound was prepared using a modification of the procedure ofWasserman et al [J. Org. Chem, 38, 1451-1455, (1973)]; triethylamine (20ml) was added to a stirred solution containing α-methyltetrahydrocinnamoyl chloride (5 g, 27.5 mmol) and ethyl ethynylether (6g, 40% soln. in hexanes, 85.7 mmol) and the resulting slurry heated to35° for 3d. The crude reaction mixture was then filtered and the residueconcentrated in vacuo. The residual oil was chromatographed (SiO₂, EtOAc20: hexanes 80) to give the title compound as a pale brown oil (4.91 g,86%). δH (CDCl₃, 300K) 7.19-7.05 (5H, m), 4.56 (1H, s), 4.09-4.00 (1H,m), 3.97-3.89 (1H, m), 2.86 (1H, d, J 14.0 Hz), 2.86 (1H, d, J 14.0 Hz),1.30 (3H, t, J 7.1 Hz), 1.24 (3H, s). m/z (ES⁺, 70V) 216.9 (MH⁺).

Intermediate 8 (+/−) 4-Benzyl-3-hydroxy-4-methyl-2-cyclobuten-1-one

Intermediate 7 (4.5 g, 20.9 mmol) and hydrochloric acid (6M, 10 ml) werestirred at room temperature for 48 h. Filtration of the resulting slurryand washing of the residue with water (3×15 ml) gave the title compoundas a pale brown powder (3.92 g, 20.8 mmol, 99%). δH (CDCl₃, 300K)7.03-6.83 (5H, m), 4.24 (1H, s), 2.52 (2H, s), 0.94 (3H, s). m/z (ES⁺,70V) 189.1 (MH⁺).

Intermediate 9 3-Cyano-4-(2-(N,N-dimethylamino)ethylen-1-yl)pyridine

A solution of 4-methyl-3-cyanopyridine [prepared acccording to Ref: J.Prakt. Chem. 338, 663 (1996)], (8.0 g, 67.8 mmol) andN,N-dimethylformamide diethyl acetal (11.0 g, 74.8 mmol) in dry DMF (50ml) was stirred at 140° under N₂ for 2 days. An additional portion ofN,N,-dimethylformamide diethyl acetal (5 g) was added and stirred at140° for 4 h. The volatiles were removed in vacuo and the obtained darkoil partitioned between EtOAc (300 ml) and water (50 ml). The phaseswere separated and the aqueous layer re-extracted with EtOAc (3×100 ml).The combined organic extracts were washed with brine (30 ml), dried(Na₂SO₄), treated with activated charcoal, filtered and evaporated invacuo to afford essentially pure title compound as a dull orange solid(10.1 g, 85%). δH (CDCl₃) 8.49 (1H, s), 8.25 (1h, d, J 5.9 Hz), 7.29(1H, d, J 13.2 Hz), 7.09 (1H, d, J 5.9 Hz), 5.25 (1H, d, J 13.2 Hz) and2.99 (6H, s); m/z (ES⁺, 70V) 174 (MH⁺).

Intermediate 10 1-Hydroxy-2,7-naphthyridine hydrochloride salt

HCl gas was bubbled through a stirred solution of Intermediate 9 (6.2 g,3.58 mmol) in glacial acetic acid (50 ml) and water (0.64 ml, 3.55 mmol)for 1-2 min. The reaction mixture was stirred in a stoppered flask at40° for 18 h. The volatiles were removed in vacuo affording a darkresidue, which was treated with water (3×20 ml) and re-evaporated invacuo. The obtained dark semi-solid was treated with 40 ml warm ethanol,ice-cooled, and the undissolved solid collected by filtration affordingthe title compound as a green coloured solid (5.2 g, 80%) δH (DMSO-d⁶)12.5 (1H, br s), 9.38 (1H, s), 8.84 (1H, d, J 7.0 Hz), 8.15 (1H, d, J7.0 Hz), 7.89 (1H, br dd, J 7.0, 5.0 Hz) and 6.85 (1H, d, J 7.0 Hz); m/z(ES⁺, 70V), 147 (MH⁺).

Intermediate 11 1-Chloro-2,7-naphthyridine

Intermediate 10 (5.2 g, 28.5 mmol) was stirred with phosphorousoxychloride (75 ml) at 1100 for 24 h. The volatiles were removed invacuo affording a dark oil which was poured into an ice-bath cooledmixture of saturated aqueous NaHCO₃ (100 ml containing 20 g solidNaHCO₃) and EtOAc (100 ml). After thorough mixing the phases wereseparated and the aqueous layer re-extracted with EtOAc (2×75 ml). Thecombined organic extracts were washed with brine (15 ml), dried (Na₂SO₄)and evaporated in vacuo to afford the title compound as a yellow solid(4.0 g, 85%) δH (CDCl₃) 9.45 (1H, s), 8.81 (1H, d, J 5.7 Hz), 8.47 (1H,d, J 5.7 Hz), 7.66 (1H, d, J 5.7 Hz) and 7.60 (1H, d, J 5.7 Hz); m/z(ES⁺, 70V) 165 and 167 (MH⁺).

Intermediate 12 Ethyl(2S)-2-amino-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]propanoate

A solution ofethyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino]propanoate (638 mg,2.07 mmol) and Intermediate 11 (310 mg, 1.88 mmol) in ethoxyethanol (2ml) was stirred at 120° for 15 min and at 100° for 1 h under nitrogen.The volatiles were removed in vacuo and the dark residue partitionedbetween EtOAc (70 ml) and saturated aqueous NaHCO₃ (10 ml). The phaseswere separated and the aqueous layer re-extracted with EtOAc (2×30 ml).The combined organic extracts were washed with brine (10 ml), dried(Na₂SO₄) and evaporated in vacuo to afford a dark foam. Chromatography(SiO₂; 5 to 10% MeOH/DCM) afforded a mixture ofethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[(t-butoxycarbonyl)amino]propanoate and some of the title compound (730 mg). This mixturewas treated with a solution of trifluoroacetic acid (5 ml) and DCM (5ml) at room temperature for 1 h. The volatiles were removed in vacuo andthe residue partitioned between EtOAc (75 ml) and saturated aqueousNaHCO₃ (20 ml). The phases were separated and the aqueous layerre-extracted with EtOAc (3×30 ml). The combined organic extracts werewashed with brine (10 ml), dried (Na₂SO₄) and evaporated in vacuo toafford an orange solid. Chromatography (SiO₂; 10% MeOH/DCM) afforded thetitle compound as a straw-coloured solid (420 mg, 60% over two steps).δH (CDCl₃) 10.70 (1H, s), 10.31 (1H, s), 9.44 (1H, d, J 5.6 Hz), 8.94(1H, d, J 5.6 Hz), 8.55 (1H, d, J 7.3 Hz), 8.54 (2H, d, J 8.5 Hz), 8.46(1H. d, J 5.6 Hz), 7.94 (2H, d, J 8.5 Hz), 4.84 (2H, q, J 7.1 Hz), 4.35(1H, t, J 6.6 Hz), 4.10 (2H, br s), 3.64 (1H, dd, J 13.5, 6.4 Hz), 3.56(1H, dd, J 13.5, 7.0 Hz) and 1.95 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 337(MH⁺).

Intermediate 13 Methyl(2S)-2-amino3-[4-(2,7-naphthyridin-1-yloxy)phenyl]propanoate

A mixture of N-(BOC)-(S)-tyrosine methyl ester (1.71 g, 5.80 mmol)potassium carbonate (0.80 g, 5.80 mmol) and Intermediate 11 (1.0 g, 6.08mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h, andat 40 for 18 h. The DMF was removed in vacuo and the residue partitionedbetween EtOAc (80 ml) and 10% aqueous Na₂CO₃ (20 ml). The phases wereseparated and the aqueous layer re-extracted with EtOAc (2×20 ml). Thecombined organic extracts were washed with brine (10 ml), dried (Na₂SO₄)and evaporated in vacuo to afford a new colourless oil. Chromatography(silica; 2.5% MeOH/DCM) afforded reasonably pure N-t-butoxycarbonylprotected title compound (1.75 g, 71%). This material was dissolved inEtOAc (40 ml) and HCl gas was bubbled through the stirred solution for 1min. then the mixture was stirred for an additional 0.5 h. The volatileswere removed in vacuo affording a yellow solid which was partitionedbetween EtOAc (80 ml) and saturated aqueous NaHCO₃ (20 ml). The phaseswere separated and the aqueous layer re-extracted with EtOAc (2×20 ml).The combined organic extracts were washed with brine (10 ml), dried(Na₂SO₄) and evaporated in vacuo. The obtained oil was chromatographed(SiO₂; 5% MeOH/DCM) to afford the title compound as a near colourlessoil (0.83 g, 62%) δH (CDCl₃) 9.77 (1H, s), 8.75 (1H, d, J 5.8 Hz), 8.10(1H, d, J 5.8 Hz), 7.58 (1H, d, J 5.8 Hz), 7.29 (2H, d, J 8.4 Hz), 7.25(1H, d, J 5.9 Hz), 7.21 (2H, d, J 8.4 Hz), 3.80-3.70 (1H, obscured m),3.72 (3H, s), 3.15 (1H, dd, J 13.6, 5.1 Hz), 2.88 (1H, dd, J 13.6, 8.0Hz) and 0.78 (2H, br s); m/z (ES⁺, 70V) 324 (MH⁺).

Intermediate 14 4-Acetonyl-3-cyanopyridine

A solution of 4-methyl-3-cyanopyridine (4 g, 33.9 mmol) andN,N-dimethylacetamide dimethylacetal (5.4 g, 40.6 mmol) in dry DMF (20ml) was stirred at 130 for 7 h. The volatiles were removed in vacuo toafford a dark oil which solidified on standing. This material waschromatographed (SiO₂; 50% EtOAc/Hexane—100% EtOAc) affording the titlecompound as an off-yellow solid (3.73 g, 69%). δH (CDCl₃) 8.87 (1H, s),8.74 (1H, d, J 5.2 Hz), 7.28 (1H, d, J 5,2 Hz), 4.00 (2H, s) and 2.36(3H, s); m/z (ES⁺, 70V) 161 (MH⁺).

Intermediate 15 1-Hydroxy-3-methyl-2,7-naphthyridine hydrochloride

HCl gas was bubbled through a stirred solution of Intermediate 14 (3.73g, 23.3 mmol) in glacial acetic acid (40 ml) for several minutes. Theflask was stoppered and reaction stirred for 18 h at ambienttemperature. The volatiles were removed in vacuo affording astraw-coloured solid. This was twice treated with water (30 ml portions)and re-evaporated in vacuo to dryness, affording the title compound(contaminated with ˜25% unidentified by-product) as a dark strawcoloured solid (4.1 g). δH (DMSO-d⁶) 12.46 (1H, br s), 9.32 (1H, s),8.71 (1H, d, J 6.5 Hz), 7.98 (1H, d, J 6.5 Hz), 6.67 (1H, s) and 2.38(3H, s); m/z (ES⁺, 70V) 161 (MH⁺). Used without further purification.

Intermediate 16 1-Chloro-3-methyl-2,7-naphthyridine

Intermediate 15 (4.1 g) was treated with phosphorus oxychloride (50 ml)at 130° for 3 h, affording a dark solution. The volatiles were removedin vacuo and the obtained dark oil extracted with ET₂O (100 ml).Saturated aqueous NaHCO₃ (ice cold; containing 10 g additional solidNaHCO₃) was poured (with CARE!) onto the crude product with swirling andice-bath cooling. After thorough shaking, addition ET₂O (80 ml) wasadded, the mixture re-shaken, and the phases separated. The aqueouslayer was re-extracted with ET₂O (2×80 ml) and the combined etherealextracts washed with brine (20 ml), dried (Na₂SO₄) and evaporated invacuo to afford an orange solid (3.6 g). Chromatography (silica; 70%EtOAc/Hexane—100% EtOAc) afforded a more-polar by-product(3-methyl-1H-pyrano[3,4-c]pyridin-1-one, (0.7 g) and the title compoundas a white solid (2.82 g, 79% from intermediate 14) δH (CDCl₃) 9.66 (1H,s), 8.73 (1H, d, J 5.8 Hz), 7.56 (1H, d, J 5.8 Hz), 7.40 (1H, s) and2.69 (3H, s); m/z (ES⁺, 70V) 179 and 181 (MH⁺).

Intermediate 17 Ethyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(3-methyl[2,7-naphthyridin-1-ylamino]phenyl}propanoatehydrochloride

Acetylchloride (55 mg, 50 ml, 0.70 mmol) was added to absolute ethanol(25 ml) and stirred for one minute. Intermediate 16 (2.50 g, 14.0 mmol)and ethyl-(S)-3-[4-aminophenyl]-2-{tert-butyloxycarbonyl]propanoate(4.31 g, 14.0 mmol) were added and the reaction mixture stirred at 60°for 2.75 h. The volatiles were removed in vacuo to afford ayellow-orange solid. This was treated with EtOAc (−25 ml), warmed,re-cooled and the precipitate collected by filtration, with ET₂Owashing, affording the title compound as a yellow solid (4.96 g, 73%).δH (CDCl₃) 10.44 (1H, br s), 10.33 (1H, br s), 8.60 (1H, d, J 6.5 Hz),8.00 (1H, d, J 6.5 Hz), 7.85 (2H, d, J 8.5 Hz), 7.28 (1H, d, J 8.0 Hz),7.23 (2H, d, J 8.5 Hz), 7.16 (1H, s), 4.19-4.01 (1H, m), 4.08 (2H, q, J7.0 Hz), 2.97 (1H, dd, J 13.8, 5.4 Hz), 2.86 (1H, dd, J 13.8, 10.0 Hz),2.50 (3H, s), 1.34 (9H, s) and 1.15 (3H, t, J 7.0 Hz); m/z (ES⁺, 70V)451 (MH⁺).

Intermediate 18Ethyl-(2S)-2-amino-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)amino]phenyl}propanoate

HCl gas was bubbled through a stirred solution of Intermediate 17 (4.95g, 10.2 mmol) for 1-2 min. After 30 min stirring at ambient temperaturethe volatiles were removed in vacuo affording a yellow powder. This wastreated with saturated aqueous NaHCO₃ (30 ml) then extracted with EtOAc(100 ml, and 3×50 ml). The combined organic extracts were washed withbrine (10 ml), dried (Na₂SO₄) and evaporated in vacuo affording thetitle compound as a yellow solid (3.56, 100%). δH (CDCl₃) 9.25 (1H, s),8.50 (1H, d, J 5.6 Hz), 7.66 (2H, d, J 8.4 Hz), 7.35 (1H, d, J 5.6 Hz),7.34 (1H, masked s), 7.14 (2H, d, J 8.4 Hz), 6.81 (1H, s), 4.12 (2H, q,J 7.2 Hz), 3.65 (1H, dd, J 7.8, 5.2 Hz), 3.02 (1H, dd, J 13.7, 5.2 Hz),2.80 (1H, dd, J 13.7, 7.8 Hz), 2.48 (3H, s), 1.56 (2H, br s) and 1.21(3H, t, J 7.2 Hz); m/z (ES⁺, 70V) 351 (MH⁺).

Intermediate 19 Ethyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoate

A mixture of N-t-butyloxycarbonyl-(S)-tyrosine ethyl ester (14.5 g, 46.9mmol), caesium carbonate (14.05 g, 43.1 mmol) and Intermediate 9 (7.0 g,39.2 mmol) in dry DMF (60 ml) was stirred at room temperature for 48 h.The reaction was diluted with ET₂O (150 ml) and filtered off. Thefiltrate was evaporated under high vacuum and the residue waschromatographed (SiO₂; 40%-60% EtOAc/Hexane) which afforded the titlecompound as a viscous, straw-coloured oil (16.2 g, 77%) δH (CDCl₃) 9.56(1H, s), 8.58 (1H, d, J 5.8 Hz), 7.39 (1H, d, J 5.8 Hz), 7.15-7.10 (4H,m), 7.00 (1H, s), 4.99-4.91 (1H, m), 4.54-4.46 (1H, m), 4.09 (2H, q, J7.1 Hz), 3.10-2.99 (2H, m), 2.36 (3H, s), 1.34 (9H, s) and 1.15 (3H, t,J 7.1 Hz); m/z (ES⁺, 70V) 452 (MH⁺).

Intermediate 20 Ethyl(2S)-2-amino-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoate

HCl gas was bubbled through a stirred solution of Intermediate 19 (16 g)in EtOAc (300 ml) until a persistent fine white precipitate formed (˜2minutes). After stirring for 0.5 h the volatiles were removed in vacuo.The obtained solid was partitioned between EtOAc (250 ml) and saturatedaqueous NaHCO₃ (80 ml plus 5 g solid NaHCO₃). The phases were separatedand the aqueous layer re-extracted with EtOAc (5×50 ml). The combinedorganic extracts were washed with brine (10 ml), dried (Na₂SO₄) andevaporated in vacuo to afford an oil. Chromatography (SiO₂; 100%EtOAC—10% EtOH/EtOAc) afforded the title compound as a viscous oil (11.1g, 89%). δH (CDCl₃) 9.71 (1H, s), 8.70 (1H, d, J 5. Hz), 7.50 (1H, d, J5.8 Hz), 7.31-7.28 (4H, m), 7.11 (1H, s), 4.23 (2H, q, J 7.1 Hz),3.79-3.72 (1H, m), 3.14 (1H, dd, J 14.1, 5.4 Hz), 2.94 (1H, dd, J 14.1,7.8 Hz), 2.47 (3H, s), 1.75-1.50 (2H, br s) and 1.30 (3H, t, J 7.1 Hz);m/z (ES⁺, 70V) 352 (MH⁺).

Intermediate 21 1-Chloro-2,6-naphthyridine

1-Hydroxy-2,6-naphthyridine (550 mg) [prepared according to the methodof Sakamoto, T. et al Chem. Pharm. Bull. 33, 626, (1985)] was stirredwith phosphorous oxychloride (10 ml) at 110° for 5 h. The volatiles wereremoved in vacuo and the residue treated carefully with ice. Afterdiluting with water (to ˜25 ml), solid NaHCO₃ was added to effectneutralisation and the product extracted into EtOAc (2×80 ml). Thecombined organic extracts were dried (MgSO₄), evaporated in vacuo, andthe crude product chromatographed (SiO₂; EtOAc) affording the titlecompound as a slightly yellow solid (420 mg, 68%). δH (CDCl₃) 9.35 (1H,s), 8.82 (1H, d, J 5.9 Hz), 8.48 (1H, d, J 5.6 Hz), 8.00 (1H, d, J 5.9Hz), 7.74 (1H, d, J 5.6 Hz); m/z (ES⁺, 70V) 165 and 167 (MH⁺).

Intermediate 22 Ethyl(2S)-2-[(tert-butoxycarbonyl)amino]3-[4-([2,6]naphthyridin-1-ylamino)phenyl]propanoate

Ethyl (S)-3-(4-aminophenyl)-2-[N-(t-butyloxycarbonyl)amino]propanoate(600 mg, 1.95 mmol), Intermediate 21 (350 mg, 2.13 mmol) and DIPEA (276mg, 372 μl, 2.13 mmol) in 2-ethoxyethanol (0.5 ml) were stirred at 130°under N₂ for several hours. The reaction was partitioned between EtOAc(70 ml) and saturated aqueous NaHCO₃ (30 ml). The phases were separatedand the aqueous layer re-extracted with EtOAc (3×30 ml). The combinedorganic extracts were washed with brine (10 ml), dried (MgSO₄) andevaporated in vacuo to afford a dark oil. Chromatography (SiO₂; 3%MeOH/DCM) gave the title compound as a dull orange foam (360 mg, 42%).δH (CDCl₃) 9.19 (1H, s), 8.67 (1H, d, J 5.9 Hz), 8.24 (1H, d, J 5.8 Hz),7.66 (1H, d, J 5.9 Hz), 7.65 (2H, d, J 8.5 Hz), 7.21 (1H, d, J 5.8 Hz),7.16 (2H, d, J 8.5 Hz), 7.15 (1H, obscured s), 5.05-4.97 (1H, m),4.60-4.51 (1H, m), 4.19 (2H, q, J 7.1 Hz), 3.17-3.04 (2H, m), 1.44 (9H,s), 1.27 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 459 (MNa⁺), 437 (MH⁺).

Intermediate 23 Ethyl(2S)-2-amino-3-[4-([2,6]naphthyridin-1-ylamino)pheny]propanoate

Intermediate 22 (360 mg) was treated with a solution of trifluoroaceticacid (10 ml) and DCM (10 ml) and stirred at RT for 2 h. The volatileswere removed in vacuo and the residue was partitioned between EtOAc (80ml) and saturated aqueous NaHCO₃ (30 ml). The phases were separated andthe aqueous layer re-extracted with EtOAc (3×30 ml). The combinedorganic extracts were dried (MgSO₄) and evaporated in vacuo to affordthe title compound as a dark orange viscous oil (280 mg, 100%). δH(CDCl₃) 9.18 (1H, s), 8.66 (1H, d, J 5.9 Hz), 8.22 (1H, d, J 5.8 Hz),7.67 (1H, d, J 5.9 Hz), 7.64 (2H, d, J 8.5 Hz), 7.22 (2H, d, J 8.5 Hz),7.19 (1H, d, J 5.8 Hz), 4.20 (2H, q, J 7.1 Hz), 3.73 (1H, dd, J 7.9, 5.1Hz), 3.10 (1H, dd, J 13.6, 5.2 Hz), 2.87 (1H, dd, J 13.6, 7.9 Hz), 1.70(3H, br s), 1.28 (3H, t, 7.1 Hz); m/z (ES⁺, 70V) 337 (MH⁺).

Intermediate 24 Methyl(2S)-2-(t-butoxycarbonyl)amino]-3-[4-([2,6]naphthyridin-1-yloxy)phenyl]propanoate

To N-(t-butyloxycarbonyl)-(S)-tyrosine methyl ester (1.42 g, 4.82 mmol)in dry DMF (10 ml) was added Intermediate 21 (0.79 g, 4.82 mmol) andcesium carbonate (1.65 g, 5.06 mmol) and the reaction stirred at 45°under N₂ for 2 days. The DMF was evaporated, EtOAc added and washed (3×)with water, dried (MgSO₄), and evaporated in vacuo. The residue waschromatographed (SiO₂; 40 to 100% EtOAc/isohexane) to afford the titlecompound as white foam (1.61 g, 82%). δH (CDCl₃) 9.29 (1H, s), 8.76 (1H,d, J 5.74 Hz), 8.17 (1H, d, J 5.74 Hz), 8.11 (1H, d, J 5.8 Hz), 7.43(1H, d, J 5.8 Hz), 7.22-7.18 (3H, m), 5.03 (1H, br s), 4.61 (1H, br s),3.75 (3H, s), 3.15-3.05 (2H, m), 1.44 (9H, s); m/z (ES⁺, 70V) MH+424.

Intermediate 25 3,5-Dichloropyridine-4-carboxylic acid

A solution of 3,5-dichloropyridine (5.00 g, 33.8 mmol) in THF (25 ml)was added to a solution of LDA [generated from nBuLi (2.5M solution inhexanes, 14.9 ml, 37.2 mmol) and diisopropylamine (4.10 g, 5.7 ml, 40.6mmol)] in THF (25 ml) at −78° under nitrogen, to give a yellow/brownslurry. The reaction was stirred for 30 min at −78° then CO₂ gas wasbubbled through to give a clear brown solution that slowly gave aprecipitate, warmed to RT over 2 h, then quenched with water (20 ml) andpartitioned between ET₂O (100 ml) and 1M NaOH (100 ml). The aqueouslayer was separated and acidified to pH 1 with concentrated hydrochloricacid and then extracted with 10% MeOH in DCM (100ml×3). The combinedorganic layers were dried (MgSO₄) and the solvent removed under vacuumto give a brown solid that was recrystallised from ethanol and driedunder vacuum to give the title compound as pinkish crystals (2.63 g,41%). δH (DMSO-d⁶) 8.74 (2H, s). δC (DMSO-d⁶) 163.5, 147.7, 141.0,126.7.

Intermediate 26 Ethyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A slurry of the compound of Intermediate 25 (51.2 g, 0.267 mol) in DCM(195 ml) and thionyl chloride (195 ml, 2.67 mol) was treated with DMF (5drops) and heated to reflux for 4 h. The reaction was concentrated invacuo and azeotroped with toluene (2×50 ml) to give a yellow solid whichwas used without further purification. A solution ofethyl-(S)-3-(4-aminophenyl)-2-(t-butoxycarbonyl amino)propionate (130.8g, 0.425 mol) in DCM (800 ml) was cooled to 0° and treated with NMM(56.0 ml, 0.51 mol), stirred for 5 minutes and then a solution of theacid chloride (98.3 g, 0.468 mol) in DCM (200 ml) was added dropwisekeeping the reaction temperature below 5° . The reaction was stirred for1 h, quenched with NaHCO₃ solution (500 ml), the organic layerseparated, washed with NaHCO₃ solution (500 ml), 10% citric acidsolution (500 ml) and NaHCO₃ solution (500 ml), dried (MgSO₄) andconcentrated in vacuo to give a yellow solid which was recrystallised(EtOAc/hexane) to give the title compound, (140 g, 69%). δH (DMSO d⁶),8.8 (2H, s), 7.55 (2H, d, J 8.5 Hz), 7.23 (2H, d, J 8.5 Hz), 4.0 (3H,m), 3.4 (2H, b s), 2.9 (1H, m), 2.8 (1H, m), 1.3 (9H, s), 1.25 (3H, t);m/z (ES⁺, 70V) 504 (MNa⁺).

Intermediate 27 Ethyl(2S)-2-amino-3-4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoatehydrochloride

A solution of the compound of Intermediate 26 (70 g, 0.146 mol) in EtOAc(500 ml) and 1,4-dioxan (50 ml) was treated with a solution of HCl inEtOAc (500 ml, 3M), and stirred at room temperature for 4 h. Thereaction was concentrated in vacuo to give a yellow solid which wastriturated with ET₂O then recrystallised (EtOAc/hexane) to give thetitle compound (59.3 g, 92%). δH (DMSO d⁶), 11.10 (1H, s), 8.70 (2H, s),7.55 (2H, d, J 8.4 Hz), 7.25 (2H, d, J 8.4 Hz), 4.10 (3H, m), 3.10 (2H,m), 1.10 (3H, m); m/z (ES⁺, 70V) 382 (MH⁺).

Intermediate 28 3-Ethoxy-7-oxaspiro[3.5]non-2-en-1-one

Tetrahydropyranyl-4-carboxylic acid (14.7 g, 0.11 mol) and DMF (0.5 ml)in DCM (150 ml) was treated dropwise with oxalyl chloride (1.1 eq, 10.9ml, 0.12 mol). After 1 h the reaction mixture was concentrated in vacuoand the residual slurry was diluted with ET₂O (200 ml) and the resultingprecipitate removed by filtration. The filtrate was treated withethoxyacetylene (40% w/w solution in hexanes, 1.3 eq, 18 ml) followeddropwise with triethylamine (25 ml, 0.19 mol) and the reaction stirredfor 11d. Filtration and concentration of the filtrate in vacuo followedby chromatography (SiO₂, 5:1 EtOAc:hexanes) gave the title compound as apale yellow oil (12.1 g, 59%). δH (CDCl₃, 300K) 4.85 (1H, s), 4.23 (2H,q, J 7.1 Hz), 3.89-3.75 (4H, m), 1.88-1.79 (4H, m), 1.47 (3H, t, J 7.1Hz); m/z (ES⁺, 70V) 182.9 (MH⁺).

Intermediate 29 7-Oxaspiro[3.5]nonane-1,3-dione

Intermediate 28 (12.1 g, 0.67 mol) and 2M hydrochloric acid (26 ml) werestirred vigorously for 24 h at room temperature. The resulting solutionwas concentrated to dryness and the residual slurry was washed with ET₂O(25 ml) to give the title compound as an off-white powder (8.93 g, 0.062mol). δH (DMSO d⁶, 300K) 4.80 (2H, s), 3.78 (4H, t, J 5.5 Hz), 2.62 (4Ht J 5.5 Hz); m/z (ES⁺, 70V) 154.9 (MH⁺).

Intermediate 30 3-Ethoxyspiro[3.6]decan-1-one

A solution of cycloheptyl carbonyl chloride (10.0 g, 0.062 mol) andethoxyacetylene (40% w/w solution in hexanes, 6.0 g, 0.083 mol, 12 ml)in diethylether (50 ml) was treated dropwise with triethylamine (20 ml,0.14 mol) and the reaction stirred for 5d at room temperature.Filtration and concentration of the filtrate in vacuo followed bychromatography (SiO₂, 5:1 EtOAc:hexanes) gave the title compound as apale yellow oil (10.5 g, 0.054 mol, 87%). δH (CDCl₃, 300K) 4.78 (1H, s),4.20 (2H, q J 7.1 Hz), 1.94-1.87 (2H, m), 1.83-1.77 (2H, m), 1.71-1.66(2H, m), 1.63-1.52 (6H, m), 1.45 (3H, t J 7.1 Hz); m/z (ES⁺, 70V) 194.9(MH⁺).

Intermediate 31 Spiro[3.6]decane-1,3-dione

Intermediate 30 (8.5 g, 0.044 mol) and 2M hydrochloric acid (30 ml) wasstirred vigorously for 24 h at room temperature. The resulting slurrywas extracted with EtOAc (3×100 ml), the extracts combined andconcentrated in vacuo, and the resulting solid was recrystallised fromdiethyl ether to give the title compound as an off-white powder (7.1 g,0.043 mol, 95%). δH (DMSO d⁶, 300K) 4.58 (2H, s), 1.75-1.29 (12H, m);m/z (ES⁺, 70V) 166.9 (MH⁺).

Intermediate 32 7-Acetyl-3-ethoxy-7-azaspiro[3.5]non-2-en-1-one

A solution of 1-acetyl piperidine-4-carbonyl chloride (5.0 g, 26.4 mmol)and ethoxyacetylene (4.0 g, 55.5 mmol) in THF (60 ml) was treateddropwise with triethylamine (7.6 ml, 55.0 mmol). The resulting slurrywas stirred at room temperature for 5d prior to filtration andconcentration of the filtrate in vacuo. Chromatography (SiO₂, 100% EtOActo 95:5 EtOAc:MeOH) gave the title compound as a white powder (3.97 g,17.8 mmol, 67%). δH (CDCl₃, 300K) 4.79 (1H, s), 4.17 (2H, q, J 7.1 Hz),3.87-3.81 (1H, m), 3.56-3.42 (3H, m), 2.02 (3H, s), 1.85-1.67 (4H, m),1.39 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 223.9 (MH⁺).

Intermediate 33 7-Acetyl-7-azaspiro[3.5]nonane-1,3-dione

Intermediate 32 (700 mg, 0.31 mmol) and hydrochloric acid (2M, 5 ml)were stirred at room temperature for 4 h. Concentration of the resultingstraw-coloured solution in vacuo gave the title compound as a pale brownwater-soluble powder (535 mg, 0.027 mmol, 87%). m/z (ES⁺, 70V) 195.9(MH⁺).

Intermediate 34 3-Ethoxy-7-methoxyspiro[3.5]non-2-en-1-one

Was prepared from 4-methoxy cyclohexanecarbonyl chloride (10 g, 52.1mmol) and ethoxyacetylene (7.5 g, 0.10 mol) according to the method ofIntermediate 1 to give the title compound as an approx. 1:1 mixture ofisomers, as a pale yellow oil (7.2 g, 34.4 mmol, 65%). δH (CDCl₃, 300K)4.81-4.79 (1H, s), 4.22-4.20 (2H q, J 7.1 Hz), 3.34-3.32 (3H, s),3.31-3.22 (1H, m), 2.04-1.56 (8H, m), 1.44-1.43 (3H t, J 7.1 Hz); m/z(ES⁺, 70V) 211.0 (MH⁺).

Intermediate 35 7-Methoxyspiro[3.5]nonane-1,3-dione

Intermediate 34 (5.0 g, 23.9 mmol) and hydrochloric acid (2M, 20 ml)were stirred at room temperature for 18 h. The resulting slurry was thendiluted with water (50 ml) and extracted with EtOAc (3×25 ml), theextracts were dried (MgSO₄), filtered, and concentrated in vacuo.Recrystallisation from diethylether gave the title compound as anoff-white powder (4.06 g, 22.4 mmol, 94%). δH (CDCl₃, 300K) 3.81 (2H,s), 3.25 (4H, m) 1.96-1.90 (2H, m), 1.86-1.79 (2H, m), 1.73-1.66 (2H,m), 1.64-1.56 (2H, m); m/z (ES⁺, 70V) 182.9 (MH⁺).

Intermediate 36 Ethyl (2S)-2-amino-3-hydroxypropanoate hydrochloride

A mixture of (2S)-2-amino-3-hydroxypropanoate (25 g, 238 mmol) andacetyl chloride (34 ml, 476 mmol) in absolute ethanol (250 ml) wasstirred at 50° for 18 hr. The volatiles were removed in vacuo until thevolume was reduced to ˜100 ml. Upon cooling the resultant precipitatewas collected, washed with ether and hexane to give the title compoundas a white powder (26.3 g, 65%). δH NMR (DMSO d⁶) 8.47 (3H, br s), 5.58(1H, dd), 4.20 (2H, q), 4.08 (1H, t), 3.81 (2H, dd), 1.23 (3H, t).

Intermediate 37 Ethyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate

Di-tert-butyl dicarbonate (10.26 g, 47 mmol) was added to a stirredmixture of Intermediate 36 (7.98 g, 47 mmol) and NaHCO₃ (8.70 g, 2.2equiv.) in dioxan/water (1:1) (80 ml) and stirred for 4.5 hr. The bulkof the solvent was removed in vacuo and the resultant slurry was treatedwith EtOAc (150 ml). The inorganics were removed by filtration withEtOAc. The filtrate was washed with 10% aq citric acid (30 ml), water(30 ml), saturated aq. NaHCO₃ (20 ml) and brine (20 ml) and dried(Na₂SO₄) and evaporared in vacuo to afford the title compound as acolourless oil (10.3 g, 94%). δH (CDCl₃) 5.45 (1H, br), 4.36 (1H, br),4.26 (2H, q), 3.94 (2H, br m), 1.47 (9H, s), 1.28 (3H, t); m/z (ES⁺,70V) 233 (MH⁺), 256 (MNa⁺).

Intermediate 38 Ethyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[(methylsulfonyl)oxy]propanoate

Methanesulphonyl chloride (730 μL, 9.43 mmol) was added to a stirred,ice-bath cooled solution of Intermediate 37 (2.0 g, 8.5 mmol) and4-methylmorpholine (1.13 ml, 10.29 mmol) in dry DCM (30 ml) and stirredfor 6 hr. The solvent was removed in vacuo and the residue treated withEtOAc (150 ml). The organics were washed with water (40 ml), 10% aqcitric acid (20 ml), water (20 ml), sat aq NaHCO₃ (20 ml), water (20ml), brine (10 ml), dried (Na₂SO₄) and evaporated in vacuo to afford acolourless glass which solidified on standing. This was treated withhexane and the solid was filtered, washed with hexane and dried under N₂atmosphere to give the title compound (2.45 g, 92%). δH (CDCl₃), 5.38(1H, br), 4.63 (3H, br m), 4.27 (2H, q), 3.03 (3H, s), 1.48 (9H, s),1.33 (3H, t); m/z (ES⁺, 70V) 333 (MNa⁺).

Intermediate 39 Ethyl(2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate

Intermediate 38 (1.09, 3.21 mmol) was stirred in acetone (10 ml) in afoil covered flask with sodium iodide (723 mg, 4.82 mmol) at RT for 18hr. The acetone was removed in vacuo and the residue partitioned betweenEtOAc (100 ml) and water (30 ml). The organics washed with brine (10ml), dried (Na₂SO₄) and evaporated in vacuo to afford a yellow oil. Thiswas purified by chromatography (SiO₂; 30% Et₂O/hexane) to afford thetitle compound as a colourless oil which solidified to a white solid(597 mg, 54%). δH (CDCl₃) 5.36 (1H, br), 4.50 (1H, br m), 4.27 (3H, m),3.59 (2H, m), 1.48 (9H, s), 1.33 (3H, t); m/z (ES⁺, 70V) 365 (MNa⁺).

Intermediate 40 Ethyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-nitropyridin-2-yl) propanoate

Zinc dust (100 mesh) (581 mg, 8.88 mmol) was heated under vacuum andthen cooled under N₂. 1,2-dibromoethane (32 μL, 0.37 mmol) and dry THF(1 ml) were added with heating to boiling. Heating was stopped and themixture stirred for 1 min. This heating and stirring was repeated twicemore. TMSCl (66 μL, 0.52 mmol) was added and stirred at 50° for ˜10mins. Intermediate 39. (2.54 g, 7.40 mmol) in dry THF (4 ml) was addedand stirred at ˜35-40° for 40 minutes. 2-bromo-5-nitropyridine (1.50 g,7.30 mmol) and PdCl₂(PPh₃)₂ (260 mg, 0.37 mmol) and dry THF (2 ml) wereadded and the reaction mixture stirred at 35° for 2 hr. The reactionmixture was partitioned between EtOAc (150 ml) and sat. aq. NH₄Cl (40ml). The phases were separated and the aqueous phase re-extracted withEtOAc (50 ml). The combined organic extracts were washed with brine (10ml), dried (Na₂SO₄) and evaporated in vacuo to afford a dark strawcoloured oil. Purification by chromatography (SiO₂; 30-70% Et₂O/hexane)afforded the title compound as a yellow oil (1.52 g, 61%). δH (CDCl₃),9.34 (1H, s), 8.39 (1H, d), 7.38 (1H, d), 5.58 (1H, br), 4.75 (1H, brm), 4.20 (2H, m), 3.47 (2H, m), 1.42 (9H, s), 1.23 (3H, t); m/z (ES⁺,70V) 339 (MH⁺).

Intermediate 41 Ethyl(2S)-3-(5-aminopyridin-2-yl)-2-[(tert-butoxycarbonyl)amino]propanoate

A stirred solution of Intermediate 40 (1.16 g, 3.42 mmol) in absoluteEtOH (20 ml) was hydrogenated at atmospheric pressure with 10% Pd oncharcoal (100 mg) for 3.5 hrs. The catalyst was removed by filtrationthrough a celite pad with DCM. The filtrate was evaporated in vacuo. Thecrude title compound was obtained as a straw-coloured oil (1.03 g, 98%)and used without further purification. δH (CDCl₃), 8.01 (1H, s), 6.92(2H, s), 5.83 (1H, br), 4.59 (1H, br m), 4.13 (2H, m), 3.63 (2H, br),3.15 (2H, br), 1.43 (9H, s), 1.21 (3H, t); m/z (ES⁺, 70V) 309 (MH⁺).

Intermediate 42 Ethyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoate.

3,5-Dichloroisonicotinoyl chloride (0.51 ml, 3.61 mmol) was added to astirred, ice-bath cooled solution of Intermediate 41 (1.06 g, 3.43 mmol)and dry pyridine (0.55 ml) in dry DCM (20 ml) and stirred at RT for 1hr. After evaporation of the solvent the residue was dissolved in EtOAc(80 ml) and washed with satuarted sodium bicarbonate (20 ml), water (10ml), brine (10 ml), then dried (Na₂SO₄) filtered and concentrated invacuo to a red-brown glass. Chromatography (SiO₂, 75% Et₂O/DCM) affordeda the title compound as tan-coloured solid (1.25 g, 75%). δH NMR (DMSOd⁶) 8.69 (2H, s), 8.58 (1H, s), 7.92 (1H, d), 7.20 (1H, d), 4.26 (1H,m), 3.97 (2H, m), 2.93 (2H, m), 1.21 (9H, s), 1.01 (3H, t); m/z (ES⁺,70V) 483 (MH⁺).

Intermediate 43 Ethyl(2S)-2-amino-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoate

Acetyl chloride (6 ml) was added to absolute EtOH (20 ml) and stirredfor 15 min., cooled to RT, then Intermediate 42 (2.74 g, 5.67 mmol)added with and stirring for 3.5 hrs. The solvent removed in vacuo. Theresultant yellow residue was treated with sat. sodium bicarbonate (10ml) and solid sodium bicarbonate till neutralised. Extraction with EtOAc(4×50 ml), drying (Na₂SO₄) and concentrated afforded he title compoundas a straw-coloured foam (2.1 g, 97%). δH NMR (DMSO d⁶) 8.67 (2H, s),8.56 (1H, s), 7.85 (1H, d), 7.16 (1H, d), 3.89 (2H, q), 3.57 (1H, dd),2.86 (1H, dd), 2.82 (1H, dd), 1.73 (2H, br), 1.00 (3H, t); m/z (ES⁺,70V) 383 (MH⁺).

Intermediate 44 3-Ethoxy-7,7-dioxo-7λ⁶-thia-spiro[3.5]non-2-en-1-one

A solution of 1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-carboxylic acid (10.2g, 57.3 mmol) [prepared according to the procedure of Org. Prep. Proc.Int. 1977, 94] and DMF (0.3 ml) in DCM (120 ml) at rt, was treateddropwise with oxalyl chloride and the resulting slurry stirred for 3d.The crude reaction was then concentrated in vacuo to give an oil whichwas re-dissolved in THF (100 ml), treated with ethoxyacetylene (10 ml,50% w/w) and triethylamine (10 ml) and the resulting slurry stirred for10d at rt. Filtration and concentration of the filtrate in vacuo gave acrude oil which was purified by chromatography (SiO₂, 30% EtOAc:hexanes)to give the title compound as a yellow oil (8.9 g, 38.6 mmol, 67%). δH(CDCl₃, 300K) 4.88 (1H, s), 4.27 (2H, q, J 7.1 Hz), 3.44-3.37 (2H, m),3.13-3.05 (2H, m), 2.47-2.40 (2H, m), 2.35-2.29 (2H, m), 1.48 (3H, t, J7.1 Hz); m/z (ES⁺, 70V) 230.9 (MH⁺).

Intermediate 45 3-Hydroxy-7,7dioxo-7λ⁶-thia-spiro[3.5]non-2-en-1-one

Intermediate 44 (8.6 g, 37.4 mmol) was stirred with 1M HCl (100 ml) for3d and the resulting solution concentrated in vacuo. The residual solidwas triturated with EtOAc to give the title compound as an off-whitesolid (5.1 g, 25.2 mmol, 68%); m/z (ES⁺, 70V) 202.9 (MH⁺).

Intermediate 46 3-Ethoxy-spiro[3.4]octa-2,6-dien-1-one

A solution of cyclopent-3-ene carboxylic acid (4.0 g, 36.0 mmol) and DMF(0.25 ml) in DCM (30 ml) at 0° was treated dropwise with oxalyl chloride(3.5 ml, 39.0 mmol). After 2 h the reaction mixture was concentrated invacuo, the residual slurry diluted with ET₂O (100 ml) and the resultingprecipitate removed by filtration and the filtrate concentrated invacuo. The resulting oil was diluted with ET₂O (50 ml), treated withethoxyacetylene (40% w/w solution in hexanes, 10 ml) followed dropwisewith triethylamine (6 ml, 44.0 mmol) and the reaction stirred for 7d.Filtration and concentration of the filtrate in vacuo followed bychromatography (SiO₂, 5:1 EtOAc:hexanes) gave the title compound as apale yellow oil (4.3 g, 73%); m/z (ES⁺, 70V) 164.9 (MH⁺).

Intermediate 47 3-Hydroxy-spiro[3.4]octa-2,6-dien-1-one

Intermediate 46 (2.0 g, 12.0 mmol) and 2M hydrochloric acid (5 ml) werestirred vigorously for 24 h at room temperature. The resulting solutionwas extracted with EtOAc (25 ml), the extracts dried (MgSO₄), filteredand concentrated in vacuo to give the title compound as an pale brownpowder (1.07 g, 7.9 mmol, 65%). δH (DMSO d⁶, 300K) 5.54 (4H, s), 4.57(2H, s), 2.52 (2H, s); m/z (ES⁺, 70V) 136.9 (MH⁺).

Intermediate 48 (±)-3-Ethoxy-4-methyl-4-phenyl-cyclobut-2-enone

A solution of (±) 2-phenylpropionic acid (10.0 g, 0.66 mmol) and DMF(0.3 ml) in DCM (150 ml) was treated dropwise with oxalyl chloride (6.4ml, 0.72 mmol). After 1 h the reaction mixture was concentrated invacuo, the residual slurry diluted with ET₂O (200 ml) and the resultingprecipitate removed by filtration. The filtrate was treated withethoxyacetylene (40% w/w solution in hexanes, 18 ml) followed dropwisewith triethylamine (25 ml, 0.19 mol) and the reaction stirred for 7d atrt. Filtration and concentration of the filtrate in vacuo followed bychromatography (SiO₂, 5:1 EtOAc:hexanes) gave the title compound as apale yellow oil (6.1 g, 45%). δH (CDCl₃, 300K) 7.45-7.24 (5H, m), 5.01(1H, s), 4.31 (2H, J 7.1 Hz), 1.67 (3H, s), 1.51 (3H, t, J 7.1 Hz); m/z(ES⁺, 70V) 202.9 (MH⁺).

Intermediate 49 (+,−)-3-Hydroxy-4-methyl-4-phenyl-cyclobut-2-enone

Intermediate 48 (4.5 g, 22.2 mmol) was hydrolysed according to themethod of Intermediate 29 to give the title compound as an off-whitepowder (3.29 g, 18.9 mmol, 85%); δH (CDCl₃, 300K) 7.53-7.21 (5H, m),4.04 (1H, d, J 21.7 Hz), 3.93 (1H, d, J 21.7 Hz), 1.62 (3H, s); m/z(ES⁺, 70V) 174.9 (MH⁺).

Intermediate 50 Cyclohexylethynyloxy-triisopropyl-silane

Prepared according to the method of Kowalski, Sankar Lal and Haque,JACS, 1986, 108, 7127-7128.

Intermediate 512-Cyclohexyl-3-triisopropylsilanyloxy-spiro[3.5]non-2-en-1-one

To a stirred solution of the compound of Intermediate 50 (5.6 g, 20mmol) in t-butylmethyl ether (50 ml) was added cyclohexylcarbonylchloride (5.3 ml, 40 mmol) and triethylamine (13 ml, 100 mmol). Themixture was stirred under reflux for 24 hours, allowed to cool andfiltered to remove triethylammonium chloride. The filtrate wasconcentrated under reduced pressure and chromatographed on silica gel,mobile phase 3% EtOAc in hexane to afford the title compound as a brownoil (5.8 g, 74%). m/z (ES⁺, 70V) 235.2 (MH⁺ of desilylated compound).

Intermediate 52 2-Cyclohexyl-spiro[3.5]nonane-1,3-dione

Intermediate 51 was stirred with 5 volumes of 2M hydrochloric acid for14 days and worked up in a similar manner to Intermediate 4 to affordthe title compound as a white crystalline solid in 40% yield. m/z (ES⁺,70V) 235.0 (MH⁺).

Intermediate 53 1-Butoxyprop-1-yne

Prepared according to the method of Nooi and Arens, Recl. Trav. Chim.Pays-Bas, 1959, 78, 284-287.

Intermediate 54 1-Butoxybut-1-yne

Prepared in a similar manner to Intermediate 53 from the appropriatestarting materials.

Intermediate 55 1-Butoxypent-1-yne

Prepared in a similar manner to Intermediate 53 from the appropriatestarting materials.

Intermediate 56 3-Butoxy-2,4,4-trimethyl-cyclobut-2-enone

Prepared in a similar manner to Intermediate 1 from Intermediate 53 in45% yield. δH (CDCl₃) 4.35 (2H, t, J 6.5 Hz), 1.79 (2H, m), 1.66 (3H,s), 1.50 (2H, m), 1.22 (6H, s), 0.99 (3H, t, J 7.4 Hz); m/z (ES⁺, 70V)183.0 (MH⁺).

Intermediate 57 3-Butoxy-2-ethyl-4,4-dimethyl-cyclobut-2-enone

Prepared in a similar manner to Intermediate 1 from Intermediate 54 in56% yield. δH (CDCl₃) 4.31 (2H, t, J 6.5 Hz), 2.07 (2H, q, J 7.6 Hz),1.80 (2H, m), 1.52 (2H, m), 1.23 (6H, s), 1.10 (3H, t, J 7.6 Hz), 1.00(3H, t, J 7.3 Hz); m/z (ES⁺, 70V) 197.0 (MH⁺).

Intermediate 58 3-Butoxy-4,4-dimethyl-2-propyl-cyclobut-2-enone

Prepared in a similar manner to Intermediate 1 from Intermediate 55 in51% yield. δH (CDCl₃) 4.30 (2H, t, J 6.5 Hz), 2.04 (2H, q, J 7.4 Hz),1.75 (2H, m), 1.50 (4H, m), 1.23 (6H, s), 1.00 (3H, t, J 7.4 Hz), 0.92(3H, t, J 7.4 Hz); m/z (ES⁺, 70V) 211.0 (MH⁺).

Intermediate 59 2,2,4-Trimethyl-cyclobutane-1,3-dione

Prepared in a similar manner to Intermediate 2 from Intermediate 56 in85% yield. δH (DMSO d⁶) 1.36 (3H, s), 1.07 (6H, s); m/z (ES⁺, 70V) 126.9(MH⁺).

Intermediate 60 4-Ethyl-2,2-dimethyl-cyclobutane-1,3-dione

Prepared in a similar manner to Intermediate 2 from Intermediate 57 in70% yield. δH (DMSO d⁶) 1.85 (2H, q, J 7.6 Hz), 1.07 (6H, s), 0.95 (3H,t, J 7.6 Hz); m/z (ES⁺, 70V) 140.9 (MH⁺).

Intermediate 61 2,2-Dimethyl-4-propyl-cyclobutane-1,3-dione

Prepared in a similar manner to Intermediate 2 from Intermediate 58 in64% yield. δH (CDCl₃) 1.96 (2H, t, J 7.3 Hz), 1.50 (2H, m), 1.28 (6H,s), 0.90 (3H, t, J 7.3 Hz); m/z (ES⁺, 70V) 154.9 (MH⁺).

Intermediate 62 3-Butoxy-2-methyl-spiro[3.5]non-2-en-1-one

Prepared in a similar manner to Intermediate 1 from Intermediate 53 in23% yield. δH (CDCl₃) 4.34 (2H, t, J 6.5 Hz), 1.77-1.25 (17H, m), 1.00(3H, t, J 7.4 Hz); m/z (ES⁺, 70V) 223.0 (MH⁺).

Intermediate 63 3-Butoxy-2-propyl-spiro[3.5]non-2-en-1-one

Prepared in a similar manner to Intermediate 1 from Intermediate 55 in67% yield. δH (CDCl₃) 4.31 (2H, t, J 6.4 Hz), 2.07 (2H, t, J 7.2 Hz),1.80-1.40 (13H, m), 1.00 (3H, t, J 7.1 Hz), 0.93 (3H, t, J 7.3 Hz); m/z(ES⁺, 70V) 251.1 (MH⁺).

Intermediate 64 2-Methyl-spiro[3.5]nonane-1,3-dione

Prepared in a similar manner to Intermediate 2 from Intermediate 62 in90% yield. δH (DMSO d⁶) 1.56 (10H, m), 1.37 (3H, s); m/z (ES⁺, 70V)166.9 (MH⁺).

Intermediate 65 2-Propyl-spiro[3.5]nonane-1,3-dione

Prepared in a similar manner to Intermediate 2 from Intermediate 63 in64% yield. δH (DMSO d⁶) 1.82 (2H, t, J 7.2 Hz), 1.58 (8H, m), 1.41 (2H,m), 1.39 (2H, q, J 7.4 Hz), 0.85 (3H, t, J 7.3 Hz); m/z (ES⁺, 70V) 195.1(MH⁺).

Intermediate 66 3-Butoxy-2-methyl-7-oxa-spiro[3.5]non-2-en-1-one

Prepared in a similar manner to Intermediate 1 from Intermediate 53 in48% yield. δH (CDCl₃) 4.30 (2H, t, J 6.5 Hz), 3.76 (4H, m), 1.70 (6H,m), 1.63 (3H, s), 1.36 (2H, m), 0.92 (3H, t, J 7.4 Hz); m/z (ES⁺, 70V)225.0 (MH⁺).

Intermediate 67 3-Butoxy-2-propyl-7-oxa-spiro[3.5]non-2-en-1-one

Prepared in a similar manner to Intermediate 1 from Intermediate 55 in79% yield. δH (CDCl₃) 4.33 (2H, t, J 6.4 Hz), 3.81 (4H, m), 2.09 (2H, t,J 7.7 Hz), 1.81 (6H, m), 1.50 (4H, m), 1.00 (3H, t, J 7.4 Hz), 0.94 (3H,t, J 7.3 Hz); m/z (ES⁺, 70V) 253.0 (MH⁺).

Intermediate 68 2-Methyl-7-oxa-spiro[3.5]nonane-1,3-dione

Prepared in a similar manner to Intermediate 2 from Intermediate 66 in51% yield. δH (DMSO d⁶) 3.67 (4H, m), 1.68 (4H, m), 1.40 (3H, s). m/z(ES⁺, 70V) 168.9 (MH⁺).

Intermediate 69 2-Propyl-7-oxa-spiro[3.5]nonane-1,3-dione

Prepared in a similar manner to Intermediate 2 from Intermediate 67 in79% yield. m/z (ES⁺, 70V) 196.9 (MH⁺).

Intermediate 70 (3-Ethoxy-prop-2-ynyl)-benzene

To a solution of ethoxy acetylene (9.95 g of 50% w/w. solution inhexanes, 70 mmol) in THF (100 ml) at −78° was added n-butyl lithium (31ml of 2.5M solution in hexanes, 78 mmol). The mixture was stirred atthis temperature for 2 h. prior to the addition of HMPA (20 ml),stirring was continued for a further 15 min. before the addition ofbenzyl bromide (9.2 ml). The reaction mixture was allowed to warm toroom temperature overnight before partitioning between EtOAc (300 ml)and water (200 ml). The organics were separated, washed with water(5×200 ml), brine (200 ml), dried (Na₂SO₄), filtered and concentrated invacuo to give the title compound as a mobile brown oil (11.1 g, 99%). δH(300 MHz, CDCl₃) 7.15-7.57 (5H, m), 4.12 (2H, q, J 7.1 Hz), 3.60 (2H,s), 1.41 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) MH⁺161.

Intermediate 71 2-Benzyl-3-ethoxy-4,4-dimethyl-cyclobut-2-enone

To a solution of Intermediate 70 (11 g, 68 mmol) in THF (200 ml) at roomtemperature was added isobutyryl chloride (11 ml) and triethylamine (19ml). The mixture was stirred at this temperature for 65 h. filtered,partitioned between EtOAc (400 ml) and water (200 ml), the organics wereseparated, washed with brine (200 ml), dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by columnchromatography (SiO₂, hexane:diethyl ether, 3:2) to give the titlecompound as a viscous clear oil (11.8 g, 75%). δH (300 MHz, CDCl₃)7.18-7.32 (5H, m), 4.27 (2H, q, J 7.1 Hz), 3.43 (2H, s), 1.36 (3H, t, J7.1 Hz), 1.28 (6H, s); m/z (ESI, 70V) MH⁺231.

Intermediate 72 4-Benzyl-2,2-dimethyl-cyclobutane-1,3-dione

Intermediate 71 (11.8 g, 51.3 mmol) was stirred in HCl (200 ml, 6M aq.)at room temperature overnight. The solid precipitate was filtered andwashed on the sinter with hexane and diethyl ether to give the titlecompound as a white powder (9.8 g, 95%). δH (300 MHz, DMSO d⁶).7.13-7.29 (5H, m), 3.20 (2H, s), 1.11 (6H, s); m/z (ES⁺, 70V) (MH⁺)213.

Intermediate 73 4-Bromomethyl-5-methyl-2-oxo-1,3-dioxolene

Prepared according to the method of Sakamoto F., Ikeda S. and TsukamotoG., Chem. Pharm. Bull., 1984, 32, 2241-2248.

Intermediate 74 Ethyl(2S)-2-tert-Butoxycarbonylamino-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoate

Intermediate 26 (500 mg, 1.04 mmol) and mCPBA (493 mg, 2.0 mmol) in DCM(10 ml) were stirred together at room temperature for 48 hrs. After thistime sodium sulfite (10% solution in water, 20 ml) was added withstirring for 5 mins, prior to separating between DCM (50 ml) and sodiumbicarbonate solution (50 ml). The organics were washed with sodiumbicarbonate solution (2×50 ml) and water (1×50 ml), dried (MgSO₄) andreduced in vacuo. The resulting orange solid was recrystalised fromEtOAc/hexane to give title compound as a pale yellow powder (350 mg). δH(DMSO d⁶) 7.78 (2H, s), 6.78 (2H, d, J 8.3 Hz), 6.46 (2H, d, J 8.4 Hz),3.55 (1H, m), 3.36 (2H, q, J 7.1 Hz), 2.31 (1H, dd J 13.8, 5.8 Hz), 2.31(1H, dd, J 13.6, 8.9 Hz), 0.60 (9H, s), 0.43 (3H, t, 3H).

Intermediate 75(S)-2-Amino-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)-amino]-phenyl}-propionicacid ethyl ester

Intermediate 74 (330 mg, 0.55 mmol) and HCl in EtOAc (2.6M) were stirredtogether at room temperature overnight. After this time the formedprecipitate was filtered off, washed with Et₂O, (3×50 ml) and then madebasic by separating between EtOAc (50 ml) and sodium bicarbonatesolution (50 ml). The organics were dried (MgSO₄) and reduced in vacuoto give title compound as white solid (185 mg). δH (CD₃OD) 8.40 (2H, s),7.43 (2H, d, J 8.6 Hz), 7.05 (2H, d, J 8.6 Hz), 3.98 (2H, q, J 7.1 Hz),2.85 (2H, m), 1.04 (3H, t, J 7.1 Hz).

EXAMPLE 1 Ethyl(2S)-2-[(4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-[4-([2,7]naphthyridin-1-yloxy)phenyl]propanoate

A solution of 3-hydroxy-4,4-dimethyl-2-cyclobutenone (57 mg, 0.51 mmol)[prepared according to the method of Wasserman, H. H. et al J. Org.Chem, 38, 1451-1455, (1973)] and the ethyl ester prepared according tothe method used to prepare Intermediate 13 (164 mg, 0.51 mmol), in1,2-dichloroethylene (5 ml), was stirred at room temperature for 72 h.The volatiles were removed in vacuo and the residue chromatographed(SiO₂; EtOAc) affording the title compound as a white solid (188 mg,0.45 mmol, 89%). δH (CDCl₃, 300K) 9.92 (1H, s), 8.75 (1H, d, J 5.7 Hz),8.60 (1H, d, J 8.6 Hz), 8.04 (1H, d, J 5.8 Hz), 7.82 (1H, d, J 5.6 Hz),7.47 (1H, d, J 5.8 Hz), 7.27 (2H, d, J 8.5 Hz), 7.16 (2H, d, J 8.5 Hz),4.31 (1H, s), 4.30-4.21 (1H, m), 3.68-3.63 (2H, q, J 7.1 Hz), 3.17 (1H,dd, J 13.6, 9.4 Hz), 2.95 (1H, dd, J 5.0, 13.6 Hz), 1.01 (3H, s), 0.93(3H, s); m/z (ES⁺, 70V) 418.1(MH⁺).

EXAMPLE 2(2S)-2-[(4,4-Dimethyl-3-oxo-1-cyclobutenyl)amino]-3-[4-([2,7]naphthyridin-1-yloxy)phenyl]propanoicacid

The compound of Example 1 (127 mg, 0.31 mmol) in THF (5 ml) was treatedin a single portion with LiOH.H₂O (13 mg, 0.32 mmol) in H₂O (1 ml) andthe reaction stirred at room temperature for 2 h. The reaction was thenquenched by the addition of HOAc (glacial, 1 ml) and the volatilesremoved in vacuo. Water (10 ml) was then added to the residual foam andstirred vigorously to effect precipitation. The precipitate was thencollected by vacuum filtration and the residue washed with water (2×5ml). Drying under vacuum gave the title compound as a fine white solid(108 mg, 0.27 mmol, 88%). δH (DMSO d⁶, 300K) 9.67 (1H, s), 8.78 (1H, d,J 5.7 Hz), 8.51 (1H, d, J 8.6 Hz), 8.09 (1H, d, J 5.8 Hz), 7.86 (1H, d,J 5.6 Hz), 7.50 (1H, d, J 5.7 Hz), 7.21 (2H, d, J 8.4 Hz), 4.17 (2H, d,J 8.4 Hz), 4.34 (1H, s), 4.18-4.14 (1H, m), 3.21 (1H, dd, J 4.9, 13.9Hz), 2.98 (1H, dd, J 13.9, 9.3 Hz), 1.06 (3H, s), 0.99 (3H, s); m/z(ES⁺, 70V) 404.1 (MH⁺).

EXAMPLE 3 Ethyl(2S)-2-[(4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-[4-([2,6]naphthyridin-1-ylamino)phenyl]propanoate

A solution of 3-hydroxy-4,4-dimethyl-2-cyclobutenone (58 mg, 5.1 mmol)and Intermediate 23 (1.01 g, 2.7 mmol) in DCM (15 ml), was stirred atroom temperature for 48 h. The volatiles were removed in vacuo and theresidue chromatographed (SiO₂; EtOAc) affording the title compound as awhite powder (990 mg, 2.3 mmol, 88%). δH (CDCl₃, 300K) 9.33 (1H, s),9.24 (1H, s), 8.69 (1H, d, J 5.9 Hz), 8.63 (1H, d, J 8.5 Hz), 8.42 (1H,dd, J 5.9, 0.8 Hz), 8.15 (1H, dd, J 5.7, 1.3 Hz), 7.85-7.80 (3H, m),7.31-7.22 (4H, m), 4.39 (1H, s), 4.24-4.21 (1H, m), 4.17 (2H, q, J 7.1Hz), 3.15 (1H, dd, J 13.8, 5.6 Hz), 3.00 (1H, dd, J 13.8, 9.0 Hz), 1.19(3H, t, J 7.1 Hz), 1.11 (3H, s), 1.05 (3H, s); m/z (ES⁺, 70V) 431.1(MH⁺).

EXAMPLE 4(2S)-2-[(4,4-Dimethyl-3-oxo-1-cyclobutenyl)amino]-3-[4-([2,6]naphthyridin-1-ylamino)phenyl]propanoicacid

The compound of Example 3 (500 mg, 1.16 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa fine white solid (421 mg, 1.04 mmol, 90%). δH (DMSO d⁶, 300K) 9.21(1H, s), 9.12 (1H, s br), 8.66 (1H, d, J 5.8 Hz), 8.38 (1H, d, J 5.8Hz), 8.18 (2H, m), 7.81 (2H, d, J 7.9 Hz), 7.27 (2H, d, J 7.9 Hz), 7.26(1H, obscured s), 4.36 (1H, s), 4.13-4.07 (1H, m), 3.20 (1H, dd, J 14.0,5.1 Hz) 3.02 (1H, dd, J 41.0, 8.7 Hz), 1.13 (3H, s), 1.09 (3H, s); m/z(ES⁺, 70V) 403.0 (MH⁺).

EXAMPLE 5 Ethyl(2S)-2-[(4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of 3-hydroxy-4,4-dimethyl-2-cyclobutenone (58 mg, 0.52 mmol)[prepared according to the method of Wasserman, H. H. et al J. Org.Chem, 38, 1451-1455, (1973)] and the free base of Intermediate 27 (200mg, 5.2 mmol), in DCM (5 ml), was stirred at room temperature for 48 h.The volatiles were removed in vacuo and the residue chromatographed(SiO₂; EtOAc) to give the title compound as a white solid (230 mg, 0.48mmol, 93%). δH (CDCl₃, 300K) 8.48 (2H, s), 8.10 (1H, s), 7.51 (2H, d, J8.2 Hz), 7.04 (2H, d, 8.2 Hz), 5.91 (1H, s), 4.43 (1H, s), 4.22 (2H, q,J 7.1 Hz), 3.17 (1H, dd, J 14.0, 5.1 Hz), 3.05 (1H, dd, J 14.0, 5.8 Hz),1.28 (3H, t, J 7.1 Hz), 1.15 (3H, s), 1.14 (3H, s); m/z (ES⁺, 70V) 476.0and 478.0 (MH⁺).

EXAMPLE 6(2S)-2-[(4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 5 (100 mg, 0.21 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa fine white solid (76 mg, 0.17 mmol, 81%). δH (DMSO d⁶, 350K) 10.5 (1H,s), 8.74 (2H, s), 7.80 (1H, broad s), 7.53 (2H, d, J 8.1 Hz), 7.25 (2H,d, J 8.1 Hz), 7.26 (1H, obscured s), 4.30 (1H, s), 3.88 (1H, m), 3.16(1H, dd, J 13.5, 4.9 Hz), 3.01 (1H, dd, J 13.5, 3.8 Hz), 1.11 (3H, s),1.07 (3H, s); m/z (ES⁺, 70V) 448.0 and 449.9 (MH⁺).

EXAMPLE 7 Methyl(2S)-2-[(4R,S)-4-methyl-3-oxo-4-propyl-1-cyclobutenyl]amino-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoate

A solution of Intermediate 2 (187 mg, 1.33 mmol) and Intermediate 20(450 mg, 1.2 mmol), in chloroform (10 ml), was stirred at 55° for 48 h.The volatiles were removed in vacuo and the residue chromatographed(SiO₂; EtOAc) to give the title compound as a white solid (539 mg, 1.17mmol, 91%) as an approx. 1:1 mixture of diastereomers. δH (CDCl₃, 300K)9.69 (1H, s), 8.69 (1H, d, J 5.7 Hz), 7.51 (1H, dd, J 9.3, 0.5 Hz),7.19-7.11 (4H, m), 5.79 (1H, d, J 7.3 Hz), 4.64 (1H, s), 4.36-4.30 (1H,m), 3.84 and 3.82 (3H, s, diastereomeric CH₃), 3.31-3.15 (2H, m), 2.45(3H, s), 1.59-1.54 (1H, m), 1.50-14 (1H, m), 1.34-1.23 (2H, m), 1.28 and1.27 (3H, s, diastereomeric CH₃), 0.91-0.86 (3H, m); m/z (ES⁺, 70V)460.1 (MH⁺).

EXAMPLE 8(2S)-2-[(4R,S)-4-Methyl-3-oxo-4-propyl-1-cyclobutenyl]amino-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoicacid

The compound of Example 7 (230 mg, 0.5 mmol) was hydrolysed in a similarmanner to the method of Example 2 to give the title compound as a finewhite solid (198 mg, 0.44 mmol, 79%) as an approx. 1:1 mixture ofdiastereomers. δH (DMSO d⁶, 300K) 13.0 (1H, s), 9.60 (1H, d, J 9.7 Hz),8.72 (1H, d, J 5.6 Hz), 8.49-8.43 (1H, m NH), 7.76 (1H, d, J 4.7 Hz),7.41-7.34 (2H, m), 7.27-7.21 (2H, m), 4.47 and 4.43 (1H, s), 4.19-4.13(1H, m), 3.29-3.23 (3H, s, and 1H as obscured m), 3.02-2.97 (1H, m),2.36 and 2.35 (3H, s), 1.50-1.10 (4H, m), 1.08 and 0.98 (3H, s),0.84-0.63 (3H, m); m/z (ES⁺, 70V) 446.1 and 447.1 (MH⁺).

EXAMPLE 9 Ethyl(2S)-2-[(4,4-dipropyl-3-oxo-1-cyclobutenyl)amino]-3-[4-([2,7]naphthyridin-1-yloxy)phenyl]propanoate

A solution of Intermediate 4 (180 mg, 1.07 mmol) and the ethyl ester ofIntermediate 13 (362 mg, 1.07 mmol), in chloroform (7 ml), was stirredat room temperature for 96 h. The volatiles were removed in vacuo andthe residue chromatographed (SiO₂, EtOAc) to give the title compound asa white solid (406 mg, 0.83 mmol, 78%). δH (CDCl₃, 300K) 9.72 (1H, s),8.71 (1H, d J 5.7 Hz), 8.04 (1H, d, J 5.8 Hz), 7.55 (1H, d, J 5.7 Hz),7.22-7.16 (4H, m), 5.67 (1H, d, J 7.9 Hz), 4.64 (1H, s), 4.26-4.16 (3H,m), 3.20 (1H, dd, J 14.1, 5.7 Hz), 3.11 (1H, dd, J 14.1, 6.6 Hz),1.58-1.01 (8H, m), 0.81 (6H, t, J 7.0 Hz); m/z (ES⁺, 70V) 488.1 and489.1 (MH⁺).

EXAMPLE10(2S)-2-[(3-Oxo-4,4-dipropyl-1-cyclobutenyl)amino]3-[4-([2,7]naphthyridin-1-yloxy)phenyl]propanoicacid

The compound of Example 9 was hydrolysed in a similar manner to themethod of Example 2 to give the title compound as a fine off-whitepowder (35 mg, 0.07 mmol, 19%). δH (DMSO d⁶, 350K) 9.68 (1H, s), 8.83(1H, d, J 5.7 Hz), 8.37 (1,d, J 8.5 Hz), 8.14 (1H, d, J 5.8 Hz), 7.91(1H, d, J 5.7 Hz), 7.55 (1H, d, J 5.8 Hz), 7.39 (2H, d, J 8.4 Hz), 7.28(2H, d, J 8.4 Hz), 4.53 (1H, s), 4.14 (1H, dd, J 9.8, 4.3 Hz), 3.25 (1H,dd, J 14.0, 4.6 Hz), 3.0 (1H, dd, J 10.3, 14.0 Hz), 1.50-0.64 (14H, m);m/z (ES⁺, 70V) 460.1 and 461.1 (MH⁺).

EXAMPLE 11 Ethyl(2S)-2-[(4R,S)-4-methyl-3-oxo-4-propyl-1-cyclobutenyl]amino-3-[4-([2,7]naphthyridin-1-yloxy)phenyl]propanoate

A solution of Intermediate 2 (300 mg, 2.1 mmol) and the ethyl ester ofIntermediate 13 (724 mg, 2.14 mmol), in DCM (15 ml), was stirred at roomtemperature for 24 h. The reaction was then diluted with DCM (30 ml) anddistilled water (20 ml) and washed successively with 1M aqueoushydrochloric acid (30 ml) water (30 ml) and saturated, aqueous sodiumhydrogen carbonate (30 ml). The organic layer was then dried (MgSO₄),filtered and concentrated in vacuo. The residual foam waschromatographed (SiO₂, EtOAc) to give the title compound as a whitepowder (827 mg, 1.8 mmol, 84%) as an approx. 1:1 mixture ofdiastereomers. δH (CDCl₃, 300K) 9.72 (1H, s), 8.71 (1H, d, J 5.7 Hz),8.04 (1H, d, J 5.8 Hz), 7.55 (1H, d, J 5.7 Hz), 7.22-7.12 (5H, m), 5.80(1H, d, J 7.6 Hz), 4.57 (1H, s), 4.28-4.20 (3H, m), 3.25-3.07 (2H, m),1.57-1.21 (7H, m), 1.18 and 1.17 (3H, s) 0.84-0.78 (3H, m); m/z (ES⁺,70V) 460.1 (MH⁺) and 482.0 (MNa⁺).

EXAMPLE 12(2S)-2-[(4R,S)-4-Methyl-3-oxo-4-propyl-1-cyclobutenyl]amino-3-[4-([2,7]naphthyridin-1-yloxy)phenyl]propanoicacid

The compound of Example 11 (600 mg, 1.31 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa fine white solid (520 mg, 1.21 mmol, 92%) as an approx. 1:1 mixture ofdiastereomers. δH (DMSO d⁶, 300K) 9.61 and 9.58 (1H, s), 8.72 (1H, d, J5.7 Hz), 8.39-8.33 (1H, m NH), 8.04-8.00 (1H, m), 7.80-7.79 (1H, m),7.45-7.33 (1H, m), 7.32-7.25 (2H, m), 7.18-7.12 (2H, m), 4.37 and 4.32(1H, s), 4.10-4.04 (1H, m), 3.17-3.12 (1H, m), 2.94-2.82 (1H, m),1.41-0.86 (4H, m), 0.99 and 0.91 (3H, s) 0.73 and 0.63 (3H, t, J 7.2Hz); m/z (ES⁺, 70V) 432.0 (MH⁺).

EXAMPLE13 Ethyl(2S)-2-[(4R,S)-4-methyl-3-oxo-4-propyl-1-cyclobutenyl]amino-3-[4-([2,6]naphthyridin-1-ylamino)phenyl]propanoate

Prepared from Intermediate 2 (200 mg, 1.43 mmol) and Intermediate 23(400 mg, 1.19 mmol), in a similar manner to the compound of Example 11to give the title compound as an approx. 1:1 mixture of diastereomers asa white powder (482 mg, 1.05 mmol, 89%). δH (CDCl₃, 300K) 9.13 (1H, s),8.61 (1H, d, J 5.9 Hz), 8.17 (1H, d, J 5.8 Hz), 7.66-7.60 (3H, m),7.19-7.04 (5H, m), 5.62 (1H, t, J 4.6 Hz), 4.51 and 4.49 (1H, s),4.25-4.19 (3H, m), 3.16-3.05 (2H, m), 1.51-1.16 (7H, m), 0.85-0.77 (3H,m); m/z (ES⁺, 70V) 459.1 (MH⁺).

EXAMPLE 14(2S)-2-[(4R,S)-4-Methyl-3-oxo-4-propyl-1-cyclobutenyl]amino-3-[4-([2,6]naphthyridin-1-ylamino)phenyl]propanoicacid

The compound of Example 13 (600 mg, 1.31 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa pale yellow powder (521 mg, 1.21 mmol, 95%) (approx. 1:1 mixture ofdiastereomers). δH (DMSO d⁶, 300K) 9.10 (1H, s), 8.55-8.53 (1H, m), 8.37and 8.31 (1H, m NH), 8.27 (1H, d, J 5.9 Hz), 7.72-7.65 (2H, m),7.15-7.08 (3H, m), 4.30 and 4.25 (1H, s), 3.99-3.94 (1H, m), 3.06-2.99(1H, m), 2.83-2.76 (1H, m), 1.34-0.96 (4H, m), 0.94 and 0.86 (3H, s),0.68 and 0.55 (3H, t, J 7.0 Hz); m/z (ES⁺, 70V) 431.0 (MH⁺).

EXAMPLE 15 Ethyl(2S)-2-[(4R,S)-4-methyl-3-oxo-4-propyl-1-cyclobutenyl]amino-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared from Intermediate 2 (120 mg, 0.86 mmol) and the free base ofIntermediate 27 (300 mg, 0.79 mmol), in a similar manner to the compoundof Example 11 to give title compound as an approx. 1:1 mixture ofdiastereomers as a white powder (318 mg, 0.63 mmol, 80%). δH (CDCl₃,300K) 8.56 (2H, s), 8.29 and 8.24 (1H, s), 7.61-7.59 (2H, m), 7.16-7.10(2H, m), 5.82-5.78 (1H, m), 4.56 (1H, s), 4.32-4.26 (3H, m), 3.29-3.23(1H, m), 3.16-3.09 (1H, m), 1.59-1.13 (7H, m), 0.89-0.84 (3H, m); m/z(ES⁺, 70V) 504.0 and 506.0 (MH⁺).

EXAMPLE 16(2S)-2-[(4R,S)-4-Methyl-3-oxo-4-propyl-1-cyclobutenyl]amino-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 15 (300 mg, 0.59 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa fine white solid (261 mg, 0.55 mmol, 92%) (approx. 1:1 mixture ofdiastereomers). δH (DMSO d⁶, 300K) 10.90 (1H, s), 8.81 (2H, s),7.60-7.56 (2H, m), 7.31-7.26 (2H, m), 4.45 and 4.42 (1H, s), 4.15-4.41(1H, m), 3.23-3.14 (1H, m), 2.99-2.89 (1H, m), 1.49-1.12 (3H, m), 1.07and 0.99 (3H, s), 0.84-0.54 (4H, m); m/z (ES⁺, 70V) 476.0 and 478.0(MH⁺).

EXAMPLE 17 Ethyl(2S)-2-[(4,4-dimethyl-3-oxo-2-hexyl-1-cyclobutenyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared from Intermediate 6 (200 mg, 1.0 mmol) and the free base ofIntermediate 27 (200 mg, 0.52 mmol), in a similar manner to the compoundof Example 11 to give the title compound as a white powder (201 mg, 0.42mmol, 72%). δH (CDCl₃, 300K) 8.99 (1H, s), 8.42 (2H, s), 7.52 (2H, d, J8.4 Hz), 7.02 (2H, d, J 7.6 Hz), 5.54 (1H, s), 4.34 (1H, s), 4.19 (2H,q, J 7.1 Hz), 3.07 (2H, br s), 1.95-1.81 (2H, br s), 1.27-0.77 (17H, m);m/z (ES⁺, 70V) 560.0 and 562.0 (MH⁺).

EXAMPLE 18(2S)-2-[(4,4-Dimethyl-3-oxo-2-hexyl-1-cyclobutenyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 17 (80 mg, 0.14 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asan off-white powder (62 mg, 0.12 mmol, 82%). δH (DMSO d⁶, 300K) 10.53(1H, s), 8.73 (2H, s), 7.60-7.56 (2H, m), 7.57 (2H, d, J 8.4 Hz), 7.30(2H, d, J 8.4 Hz), 4.14-4.12 (1H, m), 3.17 (1H, dd, J 13.9, 4.8 Hz),3.03 (1H, dd, J 13.0, 9.1 Hz), 1.87 (2H, t, J 7.3 Hz), 1.41-1.25 (9H,m), 1.15-0.86 (8H, m); m/z (ES⁺, 70V) 532.0 and 534.0 (MH⁺).

EXAMPLE 19 Ethyl(2S)-2-[(4,4-dimethyl-3-oxo-2-hexyl-1-cyclobutenyl)amino]-3-[4-([2,7]naphthyridin-1-yloxy)phenyl]propanoate

Prepared from Intermediate 6 (200 mg, 1.0 mmol) and the ethyl ester ofIntermediate 13 (200 mg, 0.59 mmol), in a similar manner to the compoundof Example 11 to give the title compound as a white powder (201 mg, 0.42mmol, 72%). δH (CDCl₃, 300K) 9.72 (1H, s), 8.71 (1H, d, J 5.7 Hz), 8.03(1H, d, J 5.8 Hz), 7.56-7.51 (1H, m), 7.27-7.17 (4H, m), 5.41 (1H, brm), 4.39 (1H, br m), 4.19 (2H, q, J 7.1 Hz), 3.15-3.12 (2H, m),1.91-1.75 (2H, m), 1.39-1.09 (18H, m), 0.81-0.74 (2H, m); m/z (ES⁺, 70V)516.1 (MH⁺).

EXAMPLE 20(2S)-2-[(4,4-Dimethyl-3-oxo-2-hexyl-1-cyclobutenyl)amino]-3-[4-([2,7]naphthyridin-1-yloxy)phenyl]propanoicacid

The compound of Example 19 (200 mg, 0.39 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa fine white solid (161 mg, 0.33 mmol, 85%). δH (DMSO d⁶, 360K) 9.62(1H, s), 8.74 (1H, d, J 5.6 Hz), 8.04 (1H, d, J 5.6 Hz), 7.82 (1H, d, J5.6 Hz), 7.47 (1H, d, J 5.5 Hz), 7.30 (2H, d, J 8.3 Hz), 7.17 (2H, d, J8.3 Hz), 4.02 (1H, br s), 3.21-3.18 (1H, m), 2.97-2.91 (1H, m), 1.74(2H, m), 1.12-0.62 (17H, m); m/z (ES⁺, 70V) 488.1 (MH⁺).

EXAMPLE21 Ethyl(2S)-2-[(4,4-dimethyl-3-oxo-2-hexyl-1-cyclobutenyl)amino]-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoate

Prepared from Intermediate 6 (200 mg, 1.0 mmol) and Intermediate 18 (300mg, 0.85 mmol), in a similar manner to the compound of Example 11 togive the title compound as a white powder (331 mg, 0.63 mmol, 73%). δH(CDCl₃, 300K) 9.70 (1H, s), 8.70 (1H, d, J 5.8 Hz), 7.51 (1H, d, J 5.8Hz), 7.26-7.19 (4H, m), 5.34 (1H, br s), 4.45 (1H, br s), 4.26 (2H, q, J7.2 Hz), 3.21 (2H, br s), 2.44 (3H, s), 2.10-1.90 (2H, m), 1.47-1.43(2H, m), 1.33-1.12 (12H, m), 0.87-0.84 (3H, m); m/z (ES⁺, 70V) 530.1(MH⁺).

EXAMPLE 22(2S)-2-[(4,4-Dimethyl-3-oxo-2-hexyl-1-cyclobutenyl)amino]-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoicacid

The compound of Example 21 (60 mg, 0.11 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa fine white solid (42 mg, 0.08 mmol, 74%). δH (DMSO d⁶, 360K) 9.59 (1H,s), 8.70 (1H, d, J 5.7 Hz), 7.70-7.68 (1H, m), 7.66 (1H, d, J 9.7 Hz),7.37 (2H, d, J 8.6 Hz), 7.31 (1H, s), 7.23 (2H, d, J 8.6 Hz), 4.18-4.16(1H, m), 3.24 (1H, dd, J 13.9, 4.4 Hz), 3.04 (1H, dd, J 13.9, 9.9 Hz),2.38 (3H, s), 1.86 (2H, t, J 7.3 Hz), 1.38-1.19 (8H, m), 1.04 (3H, s),0.99 (3H, s), 0.83-0.79 (3H, m); m/z (ES⁺, 70V) 502.1 (MH⁺).

EXAMPLE 23 Ethyl(2S)-2-[(4R,S)-4-benzyl-4-methyl-3-oxo-1-cyclobutenyl]amino-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoate

Prepared from Intermediate 8 (200 mg, 1.0 mmol) and Intermediate 20 (300mg, 0.85 mmol), in a similar manner to the compound of Example 11 togive the title compound as a white powder (412 mg, 0.79 mmol, 92%) as anapprox. 1:1 mixture of diastereomers. δH (CDCl₃, 300K) 9.70 (1H, d, J4.9 Hz), 8.71 and 8.70 (1H, d, J 5.8 Hz), 7.51 (1H, d, J 5.8 Hz),7.31-7.08 (11H, m), 5.88-5.82 (1H, m), 4.60 and 4.50 (1H, s), 4.33-4.28(1H, m), 4.26-4.16 (2H, m), 3.25-3.07 (2H, m), 2.98-2.83 (2H, m), 2.45and 2.40 (3H, s), 1.35-1.21 (6H, m); m/z (ES⁺, 70V) 522.1 (MH⁺).

EXAMPLE 24(2S)-2-[(4R,S)-4-Benzyl-4-methyl-3-oxo-1-cyclobutenyl]amino-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoicacid

The compound of Example 23 (250 mg, 0.48 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa fine white solid (221 mg, 0.45 mmol, 94%) as an approx. 1:1 mixture ofdiastereomers. δH (DMSO d⁶, 360K) 9.72 (1H, m), 8.81 (1H, m), 8.03 (1H,m), 7.82-7.77 (1H, br m), 7.46-7.20 (9H, m), 4.49 and 4.41 (1H, s), 4.21(1H, m), 3.39-3.30 (1H, m), 3.21-3.14 (1H, m), 3.01-2.87 (2H, m), 2.51(3H, s), 1.29 and 1.24 (3H, s); m/z (ES⁺, 70V) 494.0 (MH⁺).

EXAMPLE 25 Ethyl(2S)-2-[(4R,S)-4-benzyl-4-methyl-3-oxo-1-cyclobutenyl]amino-3-4-[(3,5-dichloroisonicotinoyl)amino]phenylpropanoate

Prepared from Intermediate 8 (185 mg, 0.98 mmol) and the free base ofIntermediate 27 (300 mg, 0.79 mmol), in a similar manner to the compoundof Example 11 to give the title compound as a white powder (387 mg, 0.70mmol, 89%) as an approx. 1:1 mixture of diastereomers. δH (CDCl₃, 300K)9.36 and 9.31 (1H, s), 8.36 and 8.35 (2H, s), 7.54 and 7.45 (1H, d, J8.4 Hz), 7.19-7.02 (8H, m), 6.09-6.03 (1H, m), 4.31 and 4.20 (1H, s),4.22-4.01 (3H, m), 3.07-2.92 (2H, m), 2.76-2.63 (2H, m), 1.35-1.15 (2H,m), 1.09 and 1.08 (3H, s); m/z (ES⁺, 70V) 551.9 and 553.9 (MH⁺).

EXAMPLE 26(2S)-2-[(4R,S)-4-Benzyl-4-methyl-3-oxo-1-cyclobutenyl]amino-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 25 (320 mg, 0.58 mmol) was hydrolysed in asimilar manner to the method of Example 12 to give the title compound asa fine white solid (277 mg, 0.53 mmol, 91%) as an approx. 1:1 mixture ofdiastereomers. δH(DMSO d⁶, 360K) 13.05 (1H, br s), 8.83 and 8.82 (2H,s), 8.67 and 8.62 (1H, d, J 8.9 Hz), 7.71 and 7.61 (2H, d, J 8.7 Hz),7.37-6.89 (9H, m), 4.32 and 4.23 (1H, s), 4.09-4.00 (1H, m), 3.20-2.64(4H, m), 1.24-1.07 (3H, m); m/z (ES⁺, 70V) 523.9 and 525.9 (MH⁺).

EXAMPLE 27 Ethyl(2S)-2-[(3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared from 1-keto-3-hydroxyspiro[3,5]-non-2-ene (400 mg, 2.6 mmol)[prepared according to the method of Wasserman, H. H. et al, J. Org.Chem., 38, 1451-1455 (1973)] and the free amine of Intermediate 27 (400mg, 1.04 mmol), in a similar manner to the compound of Example 11 togive the title compound as a white powder (512 mg, 0.99 mmol, 95%). δH(CDCl₃, 300K) 10.86 (1H, s), 8.78 (2H, s), 8.34 (1H, d, J 8.5 Hz), 7.56(2H, d, J 8.5 Hz), 7.25 (2H, d, J 8.5 Hz), 4.36 (1H, s), 4.20-4.11 (3H,m), 3.13 (1H, dd, J 13.8, 5.3 Hz), 3.00 (1H, dd, J 9.2, 13.8 Hz),1.67-1.19 (10H, m), 1.17 (3H, t, J 4.1 Hz); m/z (ES⁺, 70V) 516.0 and518.0 (MH⁺).

EXAMPLE 28(2S)-2-[(3-Oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 27 (700 mg, 1.36 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa fine white solid (627 mg, 1.28 mmol, 95%). δH (DMSO d⁶, 360K) 10.54(1H, s), 8.73 (2H, s), 7.81 (1H, d, J 8.4 Hz), 7.56 (2H, d, J 8.5 Hz),7.27 (2H, d, J 8.5 Hz), 4.39 (1H, s), 4.12-4.05 (1H, m), 3.19 (1H, dd, J13.9, 5.1 Hz), 3.00 (1H, dd, J 13.9, 8.8 Hz), 1.94-1.24 (10H, m); m/z(ES⁺, 70V) 488.0 and 490.0 (MH⁺).

Example 29 Ethyl(2S)-2-[(3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoate

Prepared from 1-keto-3-hydroxyspiro[3,5]-non-2-ene (400 mg, 2.6 mmol)and Intermediate 20 (400 mg, 1.14 mmol), in a similar manner to thecompound of Example 11 to give the title compound as a white powder (497mg, 1.02 mmol, 89%). δH (CDCl₃, 300K) 9.62 (1H, s), 8.72 (1H, d, J 5.7Hz), 7.99 (1H, d, J 8.6 Hz), 7.73 (1H, dd, J 5.7, 0.9 Hz), 7.37-7.34(3H, m), 7.28-7.24 (2H, m), 4.42 (1H, s), 4.26-4.18 (3H, m), 3.25 (1H,dd, J 14.0, 5.6 Hz), 3.12 (1H, dd, J 14.0, 9.1 Hz), 2.42 (3H, s),1.72-1.55 (10H, m), 1.25 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 486.1 (MH⁺).

EXAMPLE 30(2S)-2-[(3-Oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3-methyl[2.7]naphthyridin-1-yl)oxy]phenyl}propanoicacid

The compound of Example 29 (300 mg, 0.62 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa fine white solid (237 mg, 0.52 mmol, 84%). δH (DMSO d⁶, 360K) 9.62(1H, s), 8.72 (1H, d, J 5.7 Hz), 7.82 (1H, d, J 6.3 Hz), 7.73 (1H, d, J5.5 Hz), 7.35 (2H, d, J 8.7 Hz), 7.25 (2H, d, J 8.7 Hz), 4.39 (1H, s),4.12 (1H, dd, J 8.7, 13.2 Hz), 3.34-3.12 (2H, m), 2.42 (3H, s),1.72-1.53 (10H, m); m/z (ES⁺, 70V) 458.0 (MH⁺).

EXAMPLE 31 Ethyl(2S)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution containing the compound of Example 27 (500 mg, 0.97 mmol) andtriethylamine (2 eq, 270 μl ) in THF (10 ml) at 0° was treated dropwisewith a solution of bromine (1.1 eq, 170 mg) in THF (5 ml). After 20 minsthe reaction was allowed to warm to room temperature prior to dilutionwith EtOAc (100 ml). The crude reaction mixture was washed withsaturated aqueous NaHCO₃ (20 ml) and brine (20 ml), dried (MgSO₄)filtered and concentrated in vacuo. The residual foam waschromatographed (SiO₂; EtOAc) to give the title compound as a whitepowder (511 mg, 0.86 mmol, 95%). δH (CDCl₃, 300K) 8.48 (2H, s), 8.05(1H, s br), 7.52 (2H, d J 8.4 Hz), 7.04 (2H, d J 8.5 Hz), 5.81 (1H, dbr, J 8.3 Hz), 4.98-4.91 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3.21 (2H, d J5.3 Hz), 1.70-1.66 (4H, m), 1.53-1.44 (4H, m), 1.28 (3H, t J 7.1 Hz),1.20-1.16 (2H, m); m/z (ES⁺, 70V) 597.9 and 595.0 (MH⁺).

EXAMPLE 32(2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 31 (511 mg, 0.86 mmol) was hydrolysed in asimilar manner to the method of Example 2 (1.3 eq, 50 mg), to give thetitle compound as a white powder (421 mg, 0.74 mmol, 87%). δH (DMSO d⁶,390K) 10.34 (1H, s), 8.67 (2H, s), 7.53 (2H, s br), 7.26 (2H, d J 8.26Hz), 4.67 (1H, m), 3.26-3.22 (1H, m), 3.13-3.08 (1H, m), 1.67-1.21 (10H,m); m/z (ES⁺, 70V) 569.9 and 567.9 (MH⁺).

EXAMPLE 33 Ethyl(2S)-2-[(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Bromine (1.1 eq, 0.32 ml) was added dropwise to a stirred solution ofthe compound of Example 5 (2.7 g, 5.67 mmol) in THF (25 ml) at roomtemperature. After 25 min the reaction was diluted with EtOAc (100 ml)and the crude reaction mixture washed with saturated aqueous NaHCO₃ (20ml) and brine (20 ml), dried (MgSO₄) filtered and concentrated in vacuo.The residual foam was chromatographed (SiO₂, EtOAc) affording the titlecompound as a pale yellow powder (2.51 g, 4.53 mmol, 76%). δH (CDCl₃,300K) 8.46 (2H, s), 8.17 (1H, s br), 7.51 (2H, d J 8.4 Hz), 7.04 (2H, dJ 8.4 Hz), 6.05 (1H, d br, J 8.4 Hz), 4.98-4.92 (1H, m), 4.22 (2H, q, J7.1 Hz), 3.21 (2H, d J 5.4 Hz), 1.28 (3H, t J 7.1 Hz), 1.14 (3H, s),1.13 (3H, s); m/z (ES⁺, 70V) 555.8 and 557.9 (MH⁺).

EXAMPLE 34(2S)-2-[(2-Bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 33 (198 mg, 0.36 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa white powder (142 mg, 0.27 mmol, 75%). δH (DMSO d⁶, 390K) 10.46 (1H,s), 8.74 (2H, s), 7.63 (2H, d J 5.74 Hz), 7.35 (2H, d J 8.26 Hz), 4.80(1H, s br), 3.32 (1H, dd J 5.14, 14.2 Hz), 3.14 (1H, dd J 8.9 Hz 14.2Hz), 1.18 (3H, s), 1.15 (3H, s); m/z (ES⁺, 70V) 527.9 and 529.8 (MH⁺).

EXAMPLE 35 Ethyl(2S)-2-[(3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(2,7)naphthyridin-1-yloxy]phenyl}propanoate

A solution of the ethyl ester of Intermediate 13 (565 mg, 1.68 mmol) and1-keto-3-hydroxyspiro[3,5]-non-2-ene (280 mg, 1.84 mmol) in DCM (20 ml)was stirred at room temperature for 24 h. Concentration in vacuo andchromatography (SiO₂, EtOAc) to give the title compound as a pale yellowpowder (730 mg, 1.55 mmol, 92%). δH (CDCl₃, 300K) 9.82 (1H, s), 8.82(1H, d J 5.7 Hz), 8.14 (1H, d J 5.9 Hz), 7.64 (1H, d J 5.8 Hz),7.25-7.17 (6H, m), 5.77 (1H, d J 7.6 Hz), 4.60 (1H, s), 4.25 (2H, q J7.1 Hz), 3.30 (1H, dd J 5.5 Hz 13.9 Hz), 3.18 (1H, dd J 5.5 Hz 13.9 Hz),1.84-1.53 (10H, m), 1.35 (3H, t J 7.1 Hz); m/z (ES⁺, 70V) 472.1 (MH⁺).

EXAMPLE 36 Ethyl(2S)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-(2,7)naphthyridin-1-yloxy]phenyl}propanoate

A stirred solution of the compound of Example 35 (300 mg, 0.637 mmol)and triethylamine (1.2 eq, 100μl) at 0° was treated dropwise with asolution of bromine in DCM (2% v/v, 2.1 ml, 1.2 eq). After 12 h thereaction was diluted with DCM (50 ml) and washed successively withsaturated aqueous NaHCO₃, dried (MgSO₄) filtered and concentrated invacuo. The residual foam was triturated with diisopropylether and theresulting solid collected and dried in vacuo to give the title compoundas a pale yellow powder (325 mg, 0.59 mmol, 95%). δH (CDCl₃, 300K) 9.83(1H, s), 8.78 (1H, d J 5.8 Hz), 8.16 (1H, d J 5.8 Hz), 7.69 (1H, d, J5.7 Hz), 7.32 (1H, d, J 5.8 Hz), 7.27 (4H, s), 5.87 (1H, d, J 8.4 Hz),5.10-5.03 (1H, m), 4.30 (2H, q, J 7.1 Hz), 3.38-3.32 (2H, m), 1.85-1.69(4H, m), 1.67-1.50 (6H, m), 1.36 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 552.0(MH⁺).

EXAMPLE 37(2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(2,7)naphthyridin-1-yloxy]phenyl}propanoicacid

The compound of Example 36 (220 mg, 0.40 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white powder (125 mg, 0.24 mmol, 60%). δH (DMSO-d⁶, 300K) 9.27 (1H,s), 8.88 (1H, d J 9.4 Hz), 8.83 (1H, d J 5.4 Hz), 8.12 (1H, d J 5.8 Hz),7.90 (1H, d J 5.7 Hz), 7.55 (1H, d J 5.8 Hz), 7.38 (2H, d J 8.4 Hz),7.27 (2H, d J 8.4 Hz), 4.83-4.79 (1H, m), 3.08-3.03 (2H, m), 1.80-1.37(8H, m), 1.19-1.12 (2H, m); m/z (ES⁺, 70V) 523.9 (MH⁺).

EXAMPLE 38 Ethyl(2S)-2-[(3-oxo-7-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared from 7-oxaspiro[3.5]nonane-1,3-dione (1.2 g, 7.8 mmol) and thefree amine of Intermediate 27 (2.67 g, 7.0 mmol) in a similar manner tothe method of Example 11, to give the title compound (3.31 g, 6.38 mmol,91%). δH (CDCl₃, 300K) 8.61 (1H, s), 8.33 (2H, s), 7.41 (2H, d J 5 Hz),6.94 (2H, d J 8.5 Hz), 6.30 (1H, s br), 4.35 (1H, s), 4.11 (2H, q J 7.1Hz) and (1H, m obscured), 5.72 (4H, m), 3.07 (1H, dd J 14.0, 5.0 Hz),2.94 (1H, dd J 14.0, 6.6 Hz), 1.75-1.66 (2H, m), 155-1.48 (2H, m), 1.17(3H, t J 7.1 Hz); m/z (ES⁺, 70V) 517.9 (MH⁺).

EXAMPLE 39 Ethyl(2S)-2-[(2-bromo-3-oxo-7-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of the compound of Example 38 (1.64 g, 3.17 mmol) andtriethylamine (0.69 g, 970 μl, 6.8 mmol) in THF (15 ml) at 0° wastreated dropwise with a solution of bromine (560 mg, 3.1 mmol) in THF (2ml). After 1 h the resulting precipitate was removed by filtration,washed several times with cold EtOAc and dried to give the titlecompound as a white powder (1.53 g, 2.56 mmol, 81%). δH (DMSO d⁶, 300K)10.90 (1H, s), 9.07 (1H, d J 9.0 Hz), 8.81 (2H, s), 7.60 (2H, d J 8.4Hz), 7.28 (2H, d J 8.4 Hz), 4.85-4.80 (1H, m), 4.21 (2H, q J 7.1 Hz),3.81-3.76 (2H, m), 3.63-3.58 (2H, m), 3.23 (1H, dd J 13.8, 4.8 Hz), 3.05(1H, dd J 13.8, 9.4 Hz), 2.07-1.94 (2H, m), 1.52-1.49 (1H, m), 1.34-1.31(1H, m), 1.24 (3H, t J 7.1 Hz); m/z (ES⁺, 70V) 597.9 and 599.9 (MH⁺).

EXAMPLE 40(2S)-2-[(2-Bromo-3-oxo-7-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 39 (575 mg, 0.96 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white powder (283 mg, 0.50 mmol, 52%). δH (DMSO d⁶, 390K) 10.88 (1H,s), 8.98 (1H, d J 9.2 Hz), 8.81 (2H, s), 7.59 (2H, d J 8.5 Hz), 7.27(2H, d J 8.5 Hz), 4.78-4.72 (1H, m), 3.82-3.75 (2H, m), 3.64-3.54 (2H,m), 3.24 (1H, dd J 13.9, 4.5 Hz), 3.01 (1H, dd J 13.8, 9.5 Hz),2.08-1.93 (2H, m), 1.52-1.48 (1H, m), 1.30-1.26 (1H, m); m/z (ES⁺, 70V)569.9 and 571.9 (MH⁺).

EXAMPLE 41 Methyl(2S)-2-{(3-oxospiro[3.5]non-1-en-1-yl)amino}-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate

To a solution of methyl(2S)-2-amino-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate (0.80 g,2.5 mmol) in DCM (10 ml) at room temperature was added1-keto-3-hydroxyspiro[3,5]-non-2-ene (0.38 g, 2.5 mmol) and the mixturestirred for 48 h. Volatiles were removed in vacuo and the residuepurified by column chromatography (SiO₂, EtOAc) to give the titlecompound as a white solid (1.05 g, 92%). δH (CDCl₃): 7.32-7.26 (3H, m),7.12 (2H, d, J 8.2 Hz), 6.92 (2H, d, J 8.3 Hz), 5.90 (1H, br d, J 8.2Hz), 4.60 (1H, s), 4.33 (1H, br), 3.86 (3H, s), 3.73 (6H, s), 3.30 (1H,dd, J 13.9, 5.3 Hz), 3.13 (1H, dd, J 13.9, 6.3 Hz), 1.82-1.33 (10H, m);m/z (ES⁺, 70V) 450.1 (MH⁺).

EXAMPLE 42(2S)-2-{(3-Oxospiro[3.5]non-1-en-1-yl)amino}-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoicacid

The compound of Example 41 (0.40 g, 0.9 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white solid (0.19 g, 45%). δH (DMSO d⁶) 8.25 (1H, d, J 8.6 Hz),7.29-7.19 (3H, m), 7.07 (2H, d, J 7.9 Hz), 6.70 (2H, d, J 8.4 Hz), 4.32(1H, s), 4.11 (1H, br), 3.61 (6H, s), 3.18 (1H, dd, J 13.7, 4.7 Hz),2.93 (1H, dd, J 13.7 9.9 Hz), 1.67-1.16 (10H, m); m/z (ES⁺, 70V) 436.1(MH⁺).

EXAMPLE 43 Methyl(2S)-2-{(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)amino}-3-(2,6-dimethoxy[11,′-biphenyl]-4-yl)propanoate

To a cooled solution (0-5°) of the compound of Example 41 (0.42 g, 0.93mmol) and triethylamine (0.14 ml, 1.03 mmol) in THF (10 ml) was added asolution of bromine (0.16 g, 1.0 mmol) in DCM (1 ml). The mixture wasstirred at this temperature for 1 h prior to partitioning between EtOAc(100 ml) and sodium hydrosulfite (100 ml, 5% aq.). The organics wereseparated, washed with water (50 ml), brine (50 ml), dried (Na₂SO₄),filtered and concentrated in vacuo to give the crude product as paleyellow foam. Column chromatography (SiO₂, 1:1 EtOAc:hexanes) gave thetitle compound as a white foam (0.45 g, 92%). δH (CDCl₃) 7.32-7.26 (3H,m), 7.13 (2H, d, J 8.1 Hz), 6.66 (2H, d, J 8.4 Hz), 5.80 (1H, br d, J8.6 Hz), 5.15-5.08 (1H, m), 3.87 (3H, s), 3.73 (6H, s), 3.35 (1H, d, J10.0 Hz), 3.31 (1H, d, J 4.9 Hz), 1.80-1.33 (10H, m); m/z (ES⁺, 70V)529.0 and 530.0 (MH⁺).

EXAMPLE 44(2S)-2-{(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino}-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoicacid

The compound of Example 43 (0.36 g, 0.7 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa white solid (0.23 g, 58%). δH (DMSO d⁶) 8.83 (1H, d, J 9.4 Hz), 7.28(1H, d, J 8.4 Hz), 7.24-7.20 (2H, m), 7.10 (2H, d, J 8.1 Hz), 6.70 (2H,d, J 8.4 Hz), 4.83-4.77 (1H, br), 3.61 (6H, s), 3.25 (1H, dd, J 13.8,9.8 Hz), 2.95 (1H, dd, J 13.8, 10.3 Hz), 1.78-1.35 (10H, m); m/z (ES⁺,70V) 516.0 and 517.0 (MH⁺).

EXAMPLE 45 Ethyl(2S)-2-[(3-oxospiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloro-isonicotinoyl)amino]phenyl}propanoate

Prepared from Intermediate 31 (400 mg, 2.4 mmol) and the free amine ofIntermediate 27 (920 mg, 2.4 mmol) in a similar manner to the method ofExample 11, to give the title compound (1.1 g, 20.7 mmol, 86%). 8H(CDCl₃, 300K) 8.57 (2H, s), 8.28 (1H, s), 7.61 (2H, d J 8.5 Hz), 7.14(2H, d J 8.5 Hz), 5.76 (1H, d J 7.5 Hz), 4.33-4.23 (3H, m), 3.25 (1H, ddJ 14.0, 5.3 Hz), 3.12 (1H, dd J 13.9, 5.7 Hz), 1.95-1.89 (2H, m),1.79-1.70 (4H, m), 1.71-1.50 (6H, m), 1.36 (3H, t J 7.1 Hz); m/z (ES⁺,70V) 530.0 (MH⁺).

EXAMPLE 46(2S)-2-[(3-Oxospiro[3.6]dec-1-en-1-yl)amino]3-{4-[(3.5-dichloroiso-nicotinoyl)amino]phenyl}propanoicacid

The compound of Example 45 (257 mg, 0.57 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white powder (257 mg, 0.51 mmol, 89%). δH (DMSO d⁶, 390K) 10.83 (1H,s), 8.84 (2H, s), 7.39 (2H, d J 8.5 Hz), 7.29 (2H, d J 8.5 Hz), 4.30(1H, s), 4.12-3.98 (1H, m), 3.15 (1H, dd J 13.9, 5.2 Hz), 2.97 (1H, dd J13.8, 9.5 Hz), 1.85-1.78 (1H, m), 1.77-1.38 (11H, m); m/z (ES⁺, 70V)502.0 (MH⁺).

EXAMPLE 47 Ethyl(2S)-2-[(2-bromo-3-oxospiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of the compound of Example 45 (988 mg, 1.87 mmol) andtriethylamine (520 μl, 3.7 mmol) in THF (20 ml) at 0° was treateddropwise with a solution of bromine (330 mg, 2.1 mmol) in THF (2 ml).After 1 h the crude reaction mixture was diluted with EtOAc (50 ml),saturated aqueous NaCHO₃ (15 ml) and saturated aqueous sodium chloride(15 ml) and the crude product extracted with EtOAc (3×20 ml). Thecombined extracts were dried (MgSO₄), concentrated in vacuo and thecrude residue chromatographed (SiO₂, 1:1 EtOAc:hexanes) to give thetitle compound as a white powder (965 mg, 1.58 mmol, 85%). δH (CDCl₃,300K) 8.61 (2H, s), 8.45 (1H, d, J 3.1 Hz), 7.63 (2H, d, J 8.2 Hz), 7.15(2H, d, J 8.2 Hz), 5.91 (1H, d, J 8.1 Hz), 5.05-5.00 (1H, m), 4.30 (2H,q, J 7.1 Hz), 3.30 (2H, d, J 5.4 Hz), 1.98-1.90 (2H, m), 1.89-1.60 (10H,m), 1.22 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 609.9 and 611.9 (MH⁺).

EXAMPLE 48(2S)-2-[(2-Bromo-3-oxospiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 47 (560 mg, 0.92 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white powder (412 mg, 0.71 mmol, 77%). δH (DMSO d⁶, 380K) 10.40 (1H,s), 8.67 (2H, s), 7.55 (2H, d, J 8.5 Hz), 7.26 (2H, d, J 8.5 Hz), 4.52(1H, br s), 3.22 (1H. dd, J 14.1, 5.3 Hz), 3.11 (1H, dd, J 13.9, 8.0Hz), 1.82-1.29 (12H, m); m/z (ES⁺, 70V) 589.1 and 583.9 (MH⁺).

EXAMPLE 49 Ethyl (2S)2-{[4,4-dimethyl-2-(phenylselenenyl)-3-oxo-1-cyclobutenyl]amino}3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A stirred solution of the compound of Example 5 (630 mg, 1.41 mmol) inTHF (15 ml) at room temperature was treated dropwise with a solution ofphenylselenenyl chloride (283 mg, 1.48 mmol). After 10 min the crudereaction mixture was diluted with EtOAc (30 ml) saturated aqueous NaCHO₃solution (50 ml) and brine (50 ml). The mixture was extracted with EtOAc(3×50 ml), the combined extracts dried (MgSO₄) and concentrated invacuo. The residual slurry was chromatographed (SiO₂, EtOAc) to give thetitle compound as a white powder (812 mg, 1.29 mmol, 91%). δH (CDCl₃,300K) 8.58 (2H, s), 7.75 (1H, s), 7.53 (2H, d, J 8.3 Hz), 7.35-7.11 (5H,m), 7.04 (2H, d, J 8.3 Hz), 6.11 (1H, d, J 8.5 Hz), 5.28-5.25 (1H, m),4.20 (2H, q, J 7.1 Hz), 3.17 (2H, m), 1.31 (6H, s), 1.28 (3H, t, J 7.1Hz); m/z (ES⁺, 70V) 631.9 (MH⁺).

EXAMPLE 50(2S)-2-{[4,4-Dimethyl-2-(phenylselenenyl)-3-oxo-1-cyclobutenyl]amino}-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 49 (600 mg, 0.95 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white powder (503 mg, 0.83 mmol, 87%). δH (DMSO d⁶, 300K) 10.86 (1H,s), 9.11 (1H, d, J 8.9 Hz), 8.81 (2H, s), 7.50 (2H, d, J 8.2 Hz), 7.21(2H, d, J 8.2 Hz), 4.96-4.92 (1H, br s), 3.13 (1H, dd, J 13.8, 4.5 Hz),2.94 (1H, dd, J 13.6, 8.7 Hz), 1.22 (3H, s), 1.14 (3H, s); m/z (ES⁺,70V) 603.9 (MH⁺).

EXAMPLE 51 Ethyl(2S)-2-[(3-oxo-7-acetyl-7-azaspiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared from Intermediate 33 (150 mg, 0.77 mmol), and the free amine ofIntermediate 27 (150 mg, 0.39 mmol) in a similar manner to the method ofExample 11, to give the title compound (143 mg, 0.26 mmol, 67%). δH(DMSO d⁶, 300K) 10.89 (1H, s), 8.89 (2H, s), 8.55-8.48 (1H, m), 7.58(2H, d, J 7.9 Hz), 7.25 (2H, d, J 7.9 Hz), 4.47 (1H, s), 4.29-4.23 (1H,m), 4.16 (2H, q, J 7.1 Hz), 3.76-3.72 (1H, m), 3.15 (1H, dd, J 13.8, 5.2Hz), 3.01-2.89 (2H, m), 2.00 (3H, s), 1.90-1.37 (6H, m), 1.21 (3H q J7.1 Hz); m/z (ES⁺, 70V) 559.0 (MH⁺).

EXAMPLE 52(2S)-2-[(3-Oxo-7-acetyl-7-azaspiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 51 (200 mg, 0.35 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white powder (91 mg, 0.16 mmol, 46%). δH (CD₃OD, 300K) 8.90 (2H, s),7.60 (2H, d, J 8.2 Hz), 7.30 (2H, J 8.2 Hz), 4.49 (1H, s), 4.33-4.27(2H, m), 3.85-3.77 (1H, m), 3.57-3.45 (1H, m), 3.37-3.31 (1H, m),3.20-3.11 (1H, m), 3.05-2.99 (1H, m), 2.11 (3H, s), 1.97-1.52 (4H, m);m/z (ES⁺, 70V) 531.0 (MH⁺).

EXAMPLE 53 Ethyl(2S)-2-[(7-methoxy-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared from Intermediate 35 (500 mg, 2.77 mmol) and the free amine ofIntermediate 27 (980 mg, 2.6 mmol) in a similar manner to the method ofExample 11, to give the title compound as an inseparable 1:1 mixture ofisomers (1.23 g, 2.25 mmol, 87%). δH (CDCl₃, 300K, 2 isomers) 9.12/8.99(1H, s), 8.51/8.50 (2H, s), 7.59/7.56 (2H, d, J 8.5 Hz), 7.08 (2H, d, J8.5 Hz), 6.21/5.98 (1H, d, J 7.9 Hz/7.6 Hz), 4.46/4.43 (1H, s),4.29/4.10 (3H, m), 3.13-3.08 (1H, m), 3.39 (1H, m), 3.30/3.29 (3H, s),3.23-3.18 (1H, m), 3.13-3.08 (1H, m), 1.97-1.58 (8H, m), 1.35-1.34 (3H,t, J 7.1 Hz); m/z (ES⁺, 70V) 546.0 (MH⁺).

EXAMPLE 54(2S)-2-[(7-Methoxy-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 53 (950 mg, 1.7 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white powder, as an approx. 1:1 mixture of isomers (812 mg, 1.57 mmol,92%). δH (DMSO d⁶, 300K) 10.57 (1H, s), 8.73 (2H, s), 7.93 (1H, br s),7.56 (2H, d, J 8.2 Hz), 7.29-7.21 (2H, m), 4.37 (1H, s), 4.08-4.04 (1H,m), 3.34 (1H, m), 3.25 (3H, s), 3.21-3.02 (2H, m), 1.92-1.34 (8H, m);m/z (ES⁺, 70V) 518.0 (MH⁺).

EXAMPLE 55 Ethyl(2S)-2-[(2-bromo-7-methoxy-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Was prepared according to the method of Example 47 from the compound ofExample 53 (1.0 g, 1.83 mmol) and bromine (322 mg, 2.0 mmol) to give thetitle compound as a powder (778 mg, 1.24 mmol, 70%). [Separation ofisomers at this stage was achieved chromatographically (SiO₂; 1:1EtOAc:hexanes to 100% EtOAc)]. δH (CDCl₃, 300K, fast eluting isomer)10.65 (1H, s), 10.74 (1H, d, J 9.2 Hz), 8.58 (2H, s), 7.36 (2H, d, J 8.6Hz), 7.06 (2H, d, J 8.6 Hz) 4.54-4.48 (1H, m), 3.18 (1H, m), 3.03-2.98(1H, m), 3.00 (3H, s), 2.78 (1H, dd, J 13.9, 10.0 Hz), 1.18-1.65 (2H,m), 1.61-1.44 (4H, m), 1.18-1.15 (1H, m), 0.92 (1H, m); m/z (ES⁺, 70V)625.9 (MH⁺).

EXAMPLE 56(2S)-2-[(2-Bromo-7-methoxy-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 55 (650 mg, 1.04 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white powder (512 mg, 0.86 mmol, 83%). δH (DMSO d⁶, 300K) 10.86 (1H,s), 9.11 (1H, d, J 8.9 Hz), 8.81 (2H, s), 7.50 (2H, d, J 8.2 Hz), 7.21(2H, d, J 8.2 Hz), 4.96-4.92 (1H, br s), 3.13 (1H, dd J, 13.8, 4.5 Hz),2.94 (1H, dd, J 13.6, 8.7 Hz), 1.22 (3H, s), 1.14 (3H, s); m/z (ES⁺,70V) 597.9 (MH⁺).

EXAMPLE 57 Ethyl(2S)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3-methyl[2.7]naphthyridin-1-yl)oxy]phenyl}propanoate

To the compound of Example 29 (0.54 g, 1.1 mmol) in THF (10 ml) at roomtemperature was added triethylamine (0.2 ml, 1.4 mmol) and a solution ofbromine (224 mg, 1.4 mmol) in DCM (1 ml). The mixture was stirredovernight and then partitioned between EtOAc (50 ml) and water (50 ml).The organics were separated, washed with sodium hydrosulfite (2×50 ml,5% aq.), water (50 ml), brine (50 ml), dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was subjected to columnchromatography (SiO₂, EtOAc) to give the title compound as a white solid(0.46 g, 73%). δH (CDCl₃) 9.75 (1H, s), 8.69 (2H, d, J 5.9 Hz), 7.64(2H, d, J 6.0 Hz), 7.25 (2H, d, J 8.2 Hz), 7.20 (2H, d, J 8.2 Hz), 5.89(1H, d, J 8.3 Hz), 5.06 (1H, dt, J 5.4, 8.2 Hz), 4.30 (2H, q, J 7.1 Hz),3.35 (2H, m), 2.50 (3H, s), 1.84-1.33 (10H, m); m/z (ES⁺, 70V) 566.1 and567.1 (MH⁺).

EXAMPLE 58(2S)-2-{(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino}-3-{4-[(3-methyl[2.7]naphthyridin-1-yl)oxy]phenyl}propanoicacid

The compound of Example 57 (0.32 g, 0.6 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white solid (0.20 g, 66%). δH (DMSO d⁶) 9.61 (1H, s), 8.88 (1H, d, J9.5 Hz), 8.72 (1H, d, J 5.7 Hz), 7.74 (1H, d, J 5.8 Hz), 7.35 (3H, c),7.24 (2H, d, J 8.6 Hz), 4.77 (1H, m), 3.18 (1H, dd, J 13.7, 4.70 Hz),3.01 (1H, dd, J 13.7, 10.4 Hz), 2.49 (3H, s), 1.78-1.12 (10H, m); m/z(ES⁺, 70V) 537.1 and 538.1 (MH⁺).

EXAMPLE 59 Ethyl(2S)-2-{[2-(phenyisulfanyl)-4,4-dimethyl-3-oxo-1-cyclobutenyl]amino}-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of the compound of Example 5 (340 mg, 0.76 mmol) in THF (25ml), at room temperature, was treated dropwise with a solutioncontaining phenyl sulphenyl chloride (122 mg, 0.84 mmol) in THF (2 ml).After 10 min the reaction mixture was poured into a mixture of EtOAc(150 ml) and saturated aqueous NaHCO₃ solution (50 ml). The organiclayer was extracted and washed with brine (25 ml), dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (SiO₂, 100% EtOAc)gave the title compound as a white powder (346 mg, 0.59 mmol, 78%). δH(CDCl₃) 8.45 (2H, s), 8.05 (1H, s), 7.43 (1H, d, J 8.4 Hz), 7.15 (2H, d,J 8.4 Hz), 7.11-7.04 (5H, m), 6.25 (1H, d, J 8.5 Hz), 5.10-5.05 (1H, m),4.09 (2H, q, J 7.1 Hz), 3.11-3.06 (2H, m), 1.18 (3H, s), 1.15 (3H, s),1.13 (3H, t, 7.1 Hz); m/z (ES⁺, 70V) 584.0 (MH⁺).

EXAMPLE 60(2S)-2-{[2-(Phenylsulfanyl)-4,4-dimethyl-3-oxo-1-cyclobutenyl]-amino}-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the ethyl ester (340 mg, 0.58 mmol) with lithium hydroxide(60 mg, 1.4 mmol), according to the method of Example 2, gave the titlecompound (296 mg, 0.53 mmol, 90%) as a white powder. δH (DMSO d⁶, 390K)10.30 (1H, br s), 8.68 (2H, s), 7.45 (2H, br s), 7.26-7.22 (2H, m),7.15-7.08 (7H, m), 4.75-4.66 (1H, m), 3.17 (1H, dd, J 14.0, 5.3 Hz),3.04 (1H, dd J 14.0, 7.7 Hz), 1.19 (3H, s), 1.16 (3H, s); m/z (ES⁺, 70V)556.0, 557.9 (MH⁺).

EXAMPLE 61 Ethyl(2S)-2-[(2-chloro-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of the compound of Example 27 (366 mg, 0.71 mmol) in THF (25ml), at room temperature, was treated portionwise with N-chlorosuccinimide (100 mg, 0.75 mmol). After 30 min the reaction mixture waspoured into a mixture of EtOAc (150 ml) and saturated aqueous NaCHO₃solution (50 ml). The organic layer was extracted and washed with brine(25 ml), dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (SiO₂; 70% EtOAc:hexanes) gave the title compound as awhite powder (312 mg, 0.56 mmol, 80%). δH (CDCl₃) 8.50 (2H, s), 7.73(1H, s), 7.53 (1H, d, J 8.4 Hz), 7.04 (2H, d, J 8.4 Hz), 5.73 (1H, d, J8.0 Hz), 4.88-4.81 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3.21-3.16 (2H, m),1.79-1.65 (4H, m), 1.51-1.36 (6H, m), 1.28 (3H, t, J 7.1 Hz); m/z (ES⁺,70V) 550.0 (MH⁺).

EXAMPLE 62(2S)-2-[(2-Chloro-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 61 (300 mg, 0.54 mmol) withlithium hydroxide (60 mg, 1.4 mmol), according to the method of Example2, gave the title compound. δH (DMSO d⁶, 390K) 10.44 (1H, br s), 8.69(2H, s), 8.05-7.85 (1H, s br), 7.54 (2H, d, J 7.8 Hz), 7.25 (2H, d, J7.8 Hz), 4.60-4.49 (1H, m), 3.21 (1H, dd, J 14.0, 5.3 Hz), 3.04 (1H, dd,J 14.0, 5.1 Hz), 1.80-1.21 (10H, m); m/z (ES⁺, 70V) 521.9, 525.9 (MH⁺).

EXAMPLE 63 Ethyl(2S)-2-[(2-iodo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

To a stirred solution of the compound of Example 27 (1.0 g, 1.9 mmol) inTHF (10 ml) at room temperature was added N-iodosuccinamide (460 mg, 2.0mmol) in one portion. After 5 minutes the mixture was concentrated invacuo and the residue triturated with a mixture of ether (10 ml) andwater (10 ml), filtered and washed with ether and water. Oven dryinggave the title compound (802 mg, 66%) as a yellow solid. δH (DMSO d⁶)8.90 (1H, d, J 9.1 Hz), 8.78 (2H, s), 7.58 (2H, d, J 8.5 Hz), 7.25 (2H,d, J 8.5 Hz), 4.91 (1H, m), 4.20 (2H, q, J 7.1 Hz), 3.30-3.00 (2H, m),1.80-1.24 (10H, m), 1.21 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 642.0 (MH⁺).

EXAMPLE 64 Ethyl(2S)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-pyridin-3-yl-spiro[3.5]non-1-en-1-ylamino)propanoate

A mixture of the compound of Example 63 (1.0 g, 1.6 mmol), 10% palladiumon charcoal (15 mg), triphenylphosphine (100 mg, 0.32 mmol), copper (1)iodide (30 mg, 0.16 mmol), 3-pyridyl tributylstannane (560 μl, 1.7 mmol)in DMF (10 ml) was heated to 100° under a nitrogen atmosphere fro 2hours. The slvent was removed by evaporation in vacuo and the residuepurified by column chromatography (SiO₂; 666:333:1EtOAc:hexane;triethylamine) to give the title compound as a yellow oil(378 mg, 41%). δH (DMSO d⁶) 8.76 (2H, s), 8.60 (1H, m), 8.30 (2H, br.s), 7.94 (1H, d, J 8.0 Hz), 7.54 (2H, m), 7.34 (2H, m), 7.10 (1H, d, J8.4 Hz), 4.34 (1H, m), 4.24 (2H, q, J 5.3 Hz), 3.25-2.95 (2H, m),1.86-1.40 (10H, m), 1.26 (3H, t, J 5.3 Hz); m/z (ES⁺, 70V) 593.0 (MH⁺).

EXAMPLE 65(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-pyridin-3-yl-spiro[3.5]non-1-en-1-ylamino)propanoicacid

The compound of Example 64 was hydrolysed in a similar manner to themethod of Example 2 to give the title compound as a white solid (76%).8H (DMSO d⁶, 400K) 10.28 (1H, s), 8.66 (2H, s), 8.59 (1H, s), 8.34 (1H,m), 7.80 (1H, m), 7.69 (1H, m), 7.51 (2H, m), 7.24 (4H, m), 4.28 (1H,m), 3.25-3.07 (2H, m), 1.90-1.50 (10H, m); m/z (ES⁺, 70V) 565.0 (MH⁺).

EXAMPLE 66 Ethyl(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-iodo-4.4-dimethyl-3-oxo-cyclobut-1-enylamino)propanoate

Prepared in a similar manner to the compound of Example 63 from thecompound of Example 5 to give the title compound as a white solid (72%).δH (DMSO d⁶) 9.17 (1H, d, J 9.1 Hz), 8.79 (2H, s), 7.58 (2H, d, J 8.5Hz), 7.29 (2H, d, J 8.5 Hz), 4.94 (1H, m), 4.20 (2H, q, J 7.1 Hz),3.25-3.00 (2H, m), 1.23 (3H, t, J 7.1 Hz), 1.12 (3H, s), 1.03 (3H, s);m/z (ES⁺, 70V) 601.8 (MH⁺).

EXAMPLE 67 Ethyl(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(4,4-dimethyl-3-oxo-2-pyridin-3-yl-cyclobut-1-enylamino)propanoate

Prepared in a similar manner to the compound of Example 64 from thecompound of Example 66 to give the title compound as a white solid(41%). δH (CDCl₃) 8.85 (1H, m), 8.57 (1H, m), 8.34 (3H, m), 7.92 (2H,m), 7.73 (2H, m), 7.28 (1H, m), 4.33 (1H, m), 4.15 (2H, q, J 7.1 Hz),3.32-3.09 (2H, m), 1.71 (3H, s), 1.33 (3H, s), 1.27 (3H, t, J 7.1 Hz);m/z (ES⁺, 70V) 553.0 (MH⁺).

EXAMPLE 68(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(4.4-dimethyl-3-oxo-2-pyridin-3-yl-cyclobut-1-enylamino)propanoicacid

The compound of Example 67 was hydrolysed in a similar manner to themethod of Example 2 to give the title compound as a white solid (43%).8H (DMSO d⁶, 400K) 10.28 (1H, br. s), 8.66 (3H, m), 8.33 (1H, m), 8.09(1H, m), 7.75 (1H, m), 7.52 (2H, m), 7.27 (3H, m), 4.25 (1H, m), 3.26(1H, m), 3.14 (1H, m), 1.22 (3H, s), 1.06 (3H, s); m/z (ES⁺, 70V) 524.9(MH⁺).

EXAMPLE 69(2S)-2-[(2-lodo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 63 was hydrolysed in a similar manner to themethod of Example 2 to give the title compound as a white solid (98%).δH (DMSO d⁶) 10.87 (1H, s), 8.84 (1H, d, J 9.3 Hz), 8.79 (2H, s), 7.58(2H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 4.87 (1H, m), 3.25 (1H, m),3.02 (1H, m), 1.70-1.25 (10H, m); m/z (ES⁺, 70V) 613.8 (MH⁺).

EXAMPLE 70(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-iodo-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)propanoicacid

The compound of Example 66 was hydrolysed in a similar manner to themethod of Example 2 to give the title compound as a white solid (95%).8H (DMSO d⁶) 10.87 (1H, s), 9.08 (1H, d, J 9.3 Hz), 8.78 (2H, s), 7.58(2H, d, J 8.5 Hz), 7.26 (2H, d, J 8.5 Hz), 4.88 (1H, m), 3.25 (1H, m),3.04 (1H, m), 1.12 (3H, s), 1.01 (3H, s); m/z (ES⁺, 70V) 573.8 (MH⁺).

EXAMPLE 71 Ethyl(2S)-3-{5-[(3.5-dichloroisonicotinoyl)amino]pyridin-2-yl}-2-[(3-oxaspiro[3.5]non-1-en-1-yl)amino]propanoate

To a solution of Intermediate 43 (470 mg, 1.22 mmol) in DCM (10 ml) wasadded spiro[3.5]nonane-1,3-dione (187 mg, 1.23 mmol) with stirred for 18hr. After evaporation of the solvent the crude product was pyrified bychromatography (silica, 3-4% MeOH/DCM) to afford the title compound as awhite foam (610 mg, 96%). δH (DMSO d⁶) 8.81 (2H, s), 8.70 (1H, s), 8.33(1H, d), 8.02 (1H, d), 7.32 (1H, d), 4.35 (1H, m), 4.13 (2H, m), 3.23(2H, m), 1.53 (8H, br), 1.37 (2H, br), 1.17 (3H, t); m/z (ES⁺, 70V) 517(MH⁺).

EXAMPLE 72 Ethyl(2S)-2-[(2-bromo-3-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoate

A solution of NBS (169 mg, 0.94 mmol) in dry DCM (5 ml) was added to astirred solution of the compound of Example 71 (490 mg, 0.94 mmol) inDCM (10 ml) at 0° C. (ice-water bath). After 30 min the solvent wasevaporated in vacuo and the residue partitioned between Et₂O (80 ml) andsaturated sodium bicarbonate (20 ml). The phases were separated and theaqueous layer re-extracted with Et₂O (40 ml). The combined organics werewashed with water (2×10 ml), brine (10 ml), dried (Na₂SO₄) andevaporated in vacuo and the residue purified by chromatography (silica,50-80% Et₂O/hexane) to give the title compound as a colourless glassfoam (501 mg, 88%). δH (DMSO d⁶) 11.17 (1H, s), 8.83 (2H, s), 8.73 (1H,s), 8.01 (1H, d), 7.34 (1H, d), 5.06 (1H, dd), 4.20 (2H, q), 3.39-3.20(2H, brm), 1.73 (1H, m), 1.57 (8H, br), 1.34 (1H, br), 1.22 (3H, t); m/z(ES⁺, 70V) 596 (MH⁺).

EXAMPLE 73 Ethyl(2S)-2-[(2-bromo-3-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoatehydrochloride

The compound of Example 72 (300 mg, 0.50 mmol) was dissolved in EtOAc(20 ml) and HCl gas bubbled through for a short time. The resultingwhite precipitate was collected by filtration, washed with Et₂O anddried to give the title compound as a white powder (155 mg, 48%). δH(DMSO d⁶) 11.32 (1H, s), 8.84 (2H, s), 8.81 (1H, s), 8.13 (1H, d), 7.43(1H, d), 5.06 (1H, dd), 4.19 (2H, q), 3.39 (1H, m), 3.28 (1H, m), 1.74(1H, m), 1.57 (8H, br), 1.35 (1H, br), 1.22 (3H, t); m/z (ES⁺, 70V) 631(MH⁺).

EXAMPLE 74(2S)-2-[(2-Bromo-3-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoicacid

The compound of Example 72 (370 mg, 0.62 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa white solid (200 mg, 56%) as light yellow solid. δH (DMSO d⁶) 11.16(1H, s), 8.83 (2H, s), 8.73 (1H, s), 8.05 (1H, d), 7.35 (1H, d), 5.00(1H, dd), 2.76 (2H, br m), 1.55 (8H, m), 1.27 (1H, br), 1.12 (1H, br);m/z (ES⁺, 70V) 568 (MH⁺).

EXAMPLE 75 Ethyl(2S)-2-[(2-chloro-3-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoate

A solution of NCS (247 mg, 1.85 mmol) in dry THF (10 ml) was added to astirred (ice-water bath cooled) solution of the compound of Example 71(800 mg, 1.54 mmol) in THF (10 ml) and DCM (10 ml). After 2 hr thesolvent was evaporated in vacuo and the residue partitioned between Et₂O(250 ml) and saturated sodium bicarbonate (30 ml). The phases wereseparated and the organic layer was washed with brine (10 ml), dried(Na₂SO₄) and evaporated in vacuo and the residue purified bychromatography (silica, 70-100% Et₂O/hexane) to give the title compoundas white foam (620 mg, 72%). δH (DMSO d⁶) 8.96 (2H, s), 8.86 (1H, s),8.20 (1H, d), 7.50 (1H, d), 5.08 (1H, m), 4.32 (2H, q), 3.53-3.31 (2H,br m), 1.72 (9H, m), 1.50 (1H, br), 1.34 (3H, t); m/z (ES⁺, 70V) 551(MH⁺).

EXAMPLE 76 Ethyl(2S)-2-[(2-chloro-3-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoatehydrochloride

The compound of Example 75 (269 mg, 0.48 mmol) was dissolved in EtOAc(20 ml) and HCl gas bubbled through for a short time. The resultingprecipitate was collected by filtration, washed with Et₂O and dried togive the title compound (230 mg, 80.3%). δH (DMSO d⁶) 11.21 (1H, s),8.83 (2H, s), 8.75 (1H, s), 8.08 (1H, d), 7.39 (1H, d), 4.95 (1H, m),4.20 (2H, q), 3.36 (1H, m), 3.26 (1H, m), 1.71 (1H, m), 1.57 (8H, br),1.35 (1H, m), 1.21 (3H, t); m/z (ES⁺, 70V) 587 (MH⁺).

EXAMPLE 77(2S)-2-[(2-Chloro-3-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoicacid

The compound of Example 72 (250 mg, 0.45 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa white powder (142 mg, 60%). δH (DMSO d⁶) 11.19 (1H, s), 8.83 (2H, s),8.74 (1H, s), 8.07 (1H, d), 7.35 (1H, d), 4.90 (1H, m), 3.37 (1H, m),3.19 (1H, m), 1.71-1.28 (10H, br m); m/z (ES⁺, 70V) 523 (MH⁺).

EXAMPLE 78 Ethyl(2S)-3-{5-[(3.5-dichloroisonicotinoyl)amino]pyridin-2-yl}-2-{(2-(methylsulfanyl)-3-oxaspiro[3.5]non-1-en-1-yl)amino}propanoate

Sulphuryl chloride (49 μL) was added dropwise to a stirred ice-bathcooled solution of dimethyl sulfide (74 μL) in THF (5 ml). The ice bathwas removed and the solution stirred for 45 min. This solution was addedto a stirred solution of the compound of Example 71 (700 mg, 1.35 mmol)in THF (10 ml) and DCM (10 ml) and stirred at RT. The reaction wasworked up in a similar manner to that of Example 79 to give the titlecompound.

EXAMPLE 79 Ethyl(2S)-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}-2-{(2-(isopropyisulfanyl)-3-oxaspiro[3.5]non-1-en-1-yl)amino}propanoate

Sulphuryl chloride (218 μL) was added dropwise to a stirred ice-bathcooled solution of isopropyl disulphide (432 μL) in THF (10 ml). The icebath removed and the mixture stood for 35 min. 5 ml of this solution wasadded to a stirred solution of the compound of Example 71 (700 mg, 1.35mmol) in THF (10 ml) and DCM (10 ml) and stirred at RT for 15 min. Thesolvent removed and the residue was partitioned between Et₂O (130 ml)and saturated sodium bicarbonate (30 ml). The phases were separated andthe organic layer was washed with brine (10 ml), dried (Na₂SO₄) andevaporated in vacuo and the residue purified by chromatography (silica,2-3% EtOH/DCM) to give the title compound as a white foam. m/z (ES⁺,70V) 591 (MH⁺).

EXAMPLE 80 Ethyl(2S)-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}-2-{(4,4-dimethyl-3-oxo-1-cyclobutenyl)amino}propanoate

To a solution of Intermediate 43 (792 mg, 2.06 mmol) in DCM (15 ml) andTHF (5 ml) was added 2,2-dimethyl-1,3-cyclobutanedione (0.27 g, 2.41mmol) with stirring for 24 hr. After evaporation of the solvent thecrude product was purified by chromatography (SiO₂, 4-8% EtOH/DCM) togive the title compound as a white foam (926 mg, 93%). δH (DMSO d⁶),8.78 (2H, s), 8.68 (1H, s), 8.53 (1H, d), 7.30 (1H, d), 4.38 (1H, s),4.33 (1H, m), 4.11 (2H, q), 3.38-3.10 (2H, m), 1.14 (3H, t), 1.04 (3H,s), 0.94 (3H, s); m/z (ES⁺, 70V) 477 (MH⁺).

EXAMPLE 81 Ethyl(2S)-2-[(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoate

Prepared from the compound of Example 80 (600 mg, 1.25 mmol) in asimilar manner to the method of Example 72 to give the title compound(530 mg, 75%) as a white foam. δH (DMSO d⁶) 9.20 (1H, s), 8.95 (2H, s),8.87 (1H, s), 8.20 (1H, d), 7.51 (1H, d), 5.19 (1H, m), 4.32 (2H, q),3.53-3.30 (2H, m), 1.34 (3H, t), 1.26 (3H, s), 1.13 (3H, s); m/z (ES⁺,70V) 556 (MH⁺).

EXAMPLE 82 Ethyl(2S)-2-[(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]-2-pyridinyl}propanoatehydrochloride

The compound of Example 81 was dissolved in EtOAc (10 ml) and HCl gasbubbled through for a short time. The resulting white precipitate wascollected by filtration, washed with EtOAc the Et₂O and dried to givethe title compound as a white powder (252 mg). δH (DMSO d⁶) 11.30 (1H,s), 9.12 (1H, d), 8.81 (2H, s), 8.80 (1H, s), 8.10 (1H, d), 7.43 (1H,d), 5.04 (1H, m), 4.18 (2H, q), 3.30 (2H, m), 1.20 (3H, t), 1.12 (3H,s), 1.00 (3H, s); m/z (ES⁺, 70V) 592 (MH⁺).

EXAMPLE 83 Ethyl(2S)-2-[(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoicacid

The compound of Example 81 (200 mg, 3.59 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa white amorphous solid (110 mg, 58%). δH (DMSO d⁶), 8.96 (1H, d), 8.81(2H, s), 8.72 (1H, s), 8.04 (1H, d), 7.34 (1H, d), 4.96 (1H, m),3.35-3.15 (2H, m), 1.11 (3H, s), 0.96 (3H, s); m/z (ES⁺, 70V) 528 (MH⁺).

EXAMPLE 84 Ethyl(2S)-2-[(2-chloro-4.4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoate

A solution of NCS (294 mg, 2.20 mmol) in dry DCM (10 ml) was added to asolution of the compound of Example 80 (869 mg, 1.82 mmol) in THF (10ml) at between −10° to 10° with stirring for 1.5 hr. After 30 min thesolvent was evaporated in vacuo and the residue purified bychromatography (SiO₂, 4-8% EtOH/DCM) to give the title compound as alight yellow foam (786 mg, 84%). δH (DMSO d⁶) 11.18 (1H, s), 9.02 (1H,d), 8.83 (2H, s), 8.75 (1H, s), 8.08 (1H, d), 7.37 (1H, d), 4.99 (1 H,m), 4.20 (2H, q), 3.40-3.21 (2H, m), 1.22 (3H, t), 1.13 (3H, s), 1.01(3H, s); m/z (ES⁺, 70V) 511 (MH⁺).

EXAMPLE 85(2S)-2-[(2-Chloro-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoicacid

The compound of Example 84 (560 mg, 1.09 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asan off-white powder (370 mg, 70%). δH (DMSO d⁶) 11.17 (1H, s), 9.94 (1H,d), 8.83 (2H, s), 8.75 (1H, s), 8.06 (1H, d), 7.35 (1H, d), 4.91 (1H,m), 3.37-3.16 (2H, m), 1.12 (3H, s), 0.97 (3H, s); mn/z (ES⁺, 70V) 483(MH⁺).

EXAMPLE 86 Ethyl(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-[2-(1-methyl-pyridin-3-yl)-3-oxo-spiro[3.5]non-1-en-1-ylamino]-propanoateiodide salt

To a stirred solution of the compound of Example 64 (126 mg, 0.21 mmol)in DMF (1 ml) was added iodomethane (14 mL, 0.23 mmol). After 18 hrs thesolvent was removed in vacuo to give the crude title compound which wasused without further purification. m/z (ES⁺, 70V) 607.0 (MH⁺).

EXAMPLE 87 Ethyl(2S)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}-2-[2-(1-methyl-piperidin-3-yl)-3-oxo-spiro[3.5]non-1-en-1-ylamino]propanoate

The compound of Example 86 (127 mg, 0.21 mmol) was dissolved in EtOH (10ml) and hydrogenated over platinum dioxide (50 mg) at room temperatureand 1 atmosphere hydrogen for 5 days. The catalyst was removed byevaporation in vacuo to afford the title compound as a yellow oil (129mg, 100%). δH (DMSO d⁶) 10.48 (1H, brs), 8.70 (2H, s), 7.59 (2H, d, J8.1 Hz), 7.30 (2H, d, J 8.1 Hz), 4.25 (1H, m), 4.22 (2H, q, J 4.0 Hz),3.23 (1H, m), 3.08 (1H, m), 1.70-1.50 (22H, m), 1.26 (3H, m); m/z (ES⁺,70V) 613.2 (MH⁺).

EXAMPLE 88(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]-phenyl}-2-[2-(1-methyl-piperidin-3-yl)-3-oxo-spiro[3.5]non-1-en-1-ylamino]propanoicacid

The compound of Example 87 was hydrolysed in a similar manner to themethod of Example 2. The product was purified by passage through a shortcolumn (RP-18-silica; 5% aqueous acetonitrile) to give the titlecompound as a yellow solid (52%). δH (DMSO d⁶) 10.47 (1H, br s), 8.70(2H, s), 7.57 (2H, d, J 7.7 Hz), 7.27 (2H, d, J 7.7 Hz), 4.13 (1H, m),3.19 (1H, m), 3.02 (1H, m), 2.27 (3H, s), 1.70-1.30 (10H, m); m/z (ES⁺,70V) 585.1 (MH⁺).

EXAMPLE 89(2S)-Ethyl-2-[(2-chloro-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A stirred solution of the compound of Example 38 (800 mg, 1.54 mmol) inTHF (25 ml) at rt was treated in several portions with N-chlorosuccinimide (226 mg, 1.69 mmol). After 1 h the crude reaction waspartitioned between EtOAc (150 ml) and brine (100 ml). The organic layerwas removed and washed with a further 100 ml of brine and the organicphase dried (MgSO₄), filtered and concentrated in vacuo. Chromatography(SiO₂, 50% EtOAc:hexanes) gave the title compound as a white powder (625mg, 1.13 mmol, 67%). δH (DMSO d⁶, 390K) 10.39 (1H, br s), 8.69 (2H, s),8.39 (1H, d, J 8.8 Hz), 7.57 (2H, s), 7.29 (2H, d, J 8.4 Hz), 4.72 (1H,m), 4.24 (2H, q, J 7.1 Hz), 3.83-3.77 (2H, m), 3.73-3.62 (2H, m), 3.28(1H, dd, J 14.2, 5.5 Hz), 2.04-1.93 (2H, m), 1.54-1.51 (1H, m),1.44-1.42 (1H, m), 1.27 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 554 (MH⁺).

EXAMPLE 90(2S)-2-[(2-Chloro-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3.5-dichloroisonicotinoyl)-amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 89 (525 mg, 0.95 mmol) withlithium hydroxide (80 mg, 1.7 mmol) according to the method of Example 2gave the title compound (412 mg, 0.79 mol, 83%). δH (DMSO d⁶, 390K)10.40 (1H, s), 8.68 (2H, s), 8.30 (1H, br s), 7.55 (2H, d, J 5.8 Hz),7.27 (2H, d, J 5.8 Hz), 4.63 (1H, m), 3.80-3.73 (2H, m), 3.69-3.61 (2H,m), 3.26 (1H, dd, J 14.1, 4.9 Hz), 3.07 (1H, dd, J 14.1, 9.1 Hz),1.97-1.90 (2H, m), 1.51-1.48 (1H, m), 1.40-1.37 (1H, m); m/z (ES⁺, 70V)524.0 (MH⁺).

EXAMPLE 91(2S)-Ethyl-2-[(2-chloro-3-oxo-spiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Was prepared according to the method of Example 89 from the compound ofExample 45 (800 mg, 1.51 mmol) and N-chloro succinimide (222 mg, 1.66mmol) to give the title compound as a white powder (625 mg, 1.11 mmol,74%). δH (DMSO d⁶, 390K) 10.40 (1H, s), 8.70 (2H, s), 8.11 (1H, br s),7.57 (2H, br s), 7.29 (2H, d, J 8.3 Hz), 4.68 (1H, m), 4.24 (2H, q, J7.1 Hz), 3.28 (1H. dd, J 5.5, 14.3 Hz), 3.12 (1H, dd, J 9.1, 14.3 Hz),1.82-1.52 (12H, m), 1.27 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 566.0 (MH⁺).

EXAMPLE 92(2S)-2-[(2-Chloro-3-oxo-spiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}-propanoicacid

Hydrolysis of the compound of Example 91 (600 mg, 1.07 mmol) withlithium hydroxide (80 mg, 1.7 mmol), according to the method of Example2, gave the title compound (512 mg, 0.95 mol, 89%). δH (DMSO d⁶, 390K)10.37 (1H, s), 8.67 (2H, s), 7.52 (2H, m), 7.25 (2H, d, J 8.3 Hz), 4.44(1H, m), 3.22 (1H, dd, J 14.0, 5.2 Hz), 3.13 (1H, dd, J 13.9, 8.0 Hz),1.98-1.41 (12H, m); m/z (ES⁺, 70V) 536.0 (MH⁺).

EXAMPLE 93 Ethyl(2S)-2-[4,4-dimethyl-2-(1-methyl-1H-tetrazol-5-ylsulfanyl)-3-oxo-cyclobut-1-enylamino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]-phenyl}propanoate

A stirred solution of the compound of Example 5 (1.03 g, 2.16 mmol) inTHF (50 ml) at rt, was treated with a slurry of1-methyl-1H-tetrazol-5-ylsulfanyl chloride (360 mg, 2.4 mmol) in DCM (2ml). After 30 min the crude reaction was partitioned between EtOAc (150ml) and saturated aqueous sodium hydrogen carbonate solution (100 ml).The organic phase was removed, washed with brine (100 ml), dried (MgSO₄)and concentrated in vacuo. Chromatography (SiO₂, EtOAc) gave the titlecompound as a white powder (1.12 g, 1.89 mmol, 88%). δH (DMSO d⁶, 390K)10.40 (1H, s), 9.08 (1H, d, J 2.6 Hz), 8.67 (2H, s), 7.55 (2H, d, J 6.2Hz), 7.24 (2H, d, J 6.2 Hz), 5.06 (1H, m), 4.17 (2H, q, J 7.1 Hz), 4.05(3H, s), 3.27 (1H, dd, J 5.5, 14.2 Hz), 3.12 (1H, dd, J 8.9, 14.2 Hz),1.23 (3H, s), 1.22 (3H, t, J 7.1 Hz), 1.20 (3H, s); m/z (ES⁺, 70V) 590.0(MH⁺).

EXAMPLE 94(2S)-2-[4,4-Dimethyl-2-(1-methyl-1H-tetrazol-5-ylsulfanyl)-3-oxo-cyclobut-1-enylamino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]-phenyl}propanoicacid

Hydrolysis of the compound of Example 93 (640 mg, 1.08 mmol) withlithium hydroxide (80 mg, 1.7 mmol), according to the method of Example2, gave the title compound (517 mg, 0.92 mol, 85%). δH (DMSO d⁶, 390K)10.41 (1H, s), 9.35 (1H, d, J 2.6 Hz), 8.67 (2H, s), 7.51 (2H, d, J 5.9Hz), 7.22 (2H, d, J 7.5 Hz), 4.93 (1H, m), 3.97 (3H, s), 3.26 (1H, dd, J5.5, 14.2 Hz), 3.09 (1H, dd, J 8.9, 14.2 Hz), 1.17 (3H, s), 1.10 (3H,s); m/z (ES⁺, 70V) 562.0 (MH⁺).

EXAMPLE 95 Ethyl(2S)-2-[(3,7,7-trioxo-7λ⁶-thia-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared from Intermediate 45 (1.1 g, 5.4 mmol) and the free base ofIntermediate 27 (2.08 mg, 5.5 mmol), in a similar manner to the compoundof Example 11 to give the title compound as a white powder (712 mg, 1.25mmol, 23%). δH (CDCl₃, 300K) 8.51 (1H, s), 8.33 (2H, s), 7.37 (2H, d, J8.2 Hz), 6.96 (2H, d, J 8.2 Hz), 4.25 (1H, s), 4.10 (2H q, J 7.1 Hz),4.01 (1H, m), 3.40-3.33 (2H, m), 3.06 (1H, dd, J 4.5, 14.2 Hz), 2.90(1H, dd J 14.1, 8.0 Hz), 2.79-2.75 (2H, m), 2.38-2.31 (2H, m), 1.99-1.96(1H, m), 1.86-1.81 (1H, m), 1.16 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 565.9(MH⁺).

EXAMPLE 96 Ethyl(2S)-2-[(2-bromo-3.7,7-troxo-7λ⁶-thia-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of the compound of Example 95 (435 mg, 0.77 mmol) in THF (18ml) at 0° was treated portionwise with N-bromo succinimide (151 mg, 0.85mmol). After 1Omin the reaction was partitioned between EtOAc (100 ml)and saturated aqueous sodium hydrogencarbonate solution (50 ml), theorganic phase removed, dried (MgSO₄) and concentrated in vacuo.Chromatography (SiO₂, 50% EtOAc:hexanes) gave the title compound as awhite powder (411 mg, 0.64 mmol, 83%). δH (DMSO d⁶, 390K) 10.43 (1H, s),9.00 (1H, d, J 8.4 Hz), 8.69 (2H, s), 7.58 (2H, d, J 6.8 Hz), 7.28 (2H,d, J 6.8 Hz), 4.85 (1H, m), 4.23 (2H, q, J 7.1 Hz), 3.37-3.25 (3H, m,overlapping), 3.13-3.03 (3H, m, overlapping), 2.56-2.45 (2H, m),2.09-1.89 (2H, m), 1.27 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 645.9 (MH⁺).

EXAMPLE 97(2S)-2-[(2-Bromo-3,7,7-trioxo-7λ⁶-thia-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 96 (410 mg, 0.63 mmol) withlithium hydroxide (31 mg, 0.7 mmol), according to the method of Example2, gave the title compound (371 mg, 0.60 mol, 95%). δH (DMSO d⁶, 390K)10.41 (1H, s), 9.35 (1H, d, J 2.6 Hz), 8.69 (2H, s), 7.55 (2H, d, J 6.7Hz), 7.27 (2H, d, J 6.7 Hz), 4.70 (1H, m), 3.37-3.25 (5H, m), 3.05 (1H,dd, J 13.3, 5.4 Hz), 2.3 (2H, m), 2.02 (1H, m), 1.92 (1H, m); m/z (ES⁺,70V) 617.8 (MH⁺).

EXAMPLE 98 Ethyl(2S)-2-[4,4-dimethyl-2-(1-methyl-1H-imidazol-2-ylsulfanyl)-3-oxo-cyclobut-1-enylamino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared from the compound of Example 5 (1.0 g, 2.1 mmol) and1-methyl-1H-imidazol-2-ylsulfenyl chloride (340 mg, 2.3 mmol), in asimilar manner to the compound of Example 93 to give title compound as awhite powder (1.03 g, 1.75 mmol, 83%). δH (DMSO d⁶, 390K) 10.84 (1H, s),9.19 (1H, d, J 9.0 Hz), 8.79 (2H, s), 7.53 (2H, d, J 8.5 Hz), 7.23 (2H,d, J 8.5 Hz), 7.21 (1H, d, J 1.1 Hz), 6.88 (1H, d, J 1.1 Hz), 5.46 (1H,m), 4.16 (2H, q, J 7.1 Hz), 3.62 (3H, s), 3.26 (1H, dd, J 14.2, 5.2 Hz),3.06 (1H, dd, J 14.2, 8.9 Hz), 1.20 (3H, t, J 7.1 Hz), 1.09 (3H, s),0.97 (3H, s); m/z (ES⁺, 70V) 590.0 (MH⁺).

EXAMPLE 99(2S)-2-[4.4-Dimethyl-2-(1-methyl-1H-imidazol-2-yllsulfanyl)-3-oxo-cyclobut-1-enylamino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 98 (760 mg, 1.29 mmol) withlithium hydroxide (100 mg, 2.2 mmol), according to the method of Example2, gave the title compound (412 mg, 0.74 mol, 57%). δH (DMSO d⁶, 390K)10.83 (1H, s), 9.11 (1H, d, J 9.0 Hz), 8.79 (2H, s), 7.51 (2H, d, J 8.5Hz), 7.23 (2H, d, J 8.5 Hz), 7.21 (1H, d, J 1.1 Hz), 6.90 (1H, d, J 1.1Hz), 5.38 (1H, m), 3.63 (3H, s), 3.25 (1H, dd, J 14.2, 5.2 Hz), 3.05(1H, dd, J 14.2, 8.9 Hz), 1.07 (3H, s), 0.96 (3H, s); m/z (ES⁺, 70V)562.0 (MH⁺).

EXAMPLE 100(2S)-Ethyl-2-[(3-thioxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of the compound of Example 27 (700 mg, 1.36 mmol) andLawesson's reagent[2,4-bis(4-methoxyphenyl)-1,2,3,4-dithiadiphosphetane2,4-disulphide](561 mg, 1.38 mmol) in toluene (25 ml) was heated to 80° for 24 h. Thecrude reaction was then partitioned between EtOAc (100 ml) and brine(100 ml). The organic phase was separated, dried (MgSO₄) andconcentrated in vacuo. Chromatography (SiO₂, EtOAc) gave the titlecompound as a yellow powder (621 mg, 1.17 mmol, 86%). δH (DMSO d⁶, 390K)10.84 (1H, s), 8.96 (1H, d J 8.9 Hz), 8.78 (2H, s), 7.56 (2H, d, J 7.9Hz), 7.25 (2H, d, J 7.9 Hz), 5.48 (1H, s), 4.37 (1H, m), 4.18 (2H, q, J7.1 Hz), 3.20 (1H, dd, J 13.9, 4.9 Hz), 3.04 (1H, dd, J 13.9, 9.9 Hz),1.96-1.87 (2H, m), 1.63-1.42 (8H, m), 1.21 (3H, t, J 7.1 Hz); m/z (ES⁺,70V) 532.0, 534.0 (MH⁺).

EXAMPLE 101(2S)-2-[(3-Thioxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dicloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 100 (340 mg, 0.66 mmol) withlithium hydroxide (30 mg, 0.67 mmol), according to the method of Example2, gave the title compound (287 mg, 0.57 mol, 86%). δH (DMSO d⁶, 390K)10.84 (1H, s), 8.87 (1H, d, J 8.8 Hz), 8.77 (2H, s), 7.54 (2H, d, J 8.3Hz), 7.24 (2H, d, J 8.3 Hz), 5.45 (1H, s), 4.23 (1H, m), 3.21 (1H, dd, J13.9, 4.4 Hz), 3.00 (1H, dd, J 13.9, 9.9 Hz), 1.96-1.87 (2H, m),1.67-1.41 (8H, m); m/z (ES⁺, 70V) 562.0 (MH⁺).

EXAMPLE 102(2S)-2-[(3-oxo-spiro[3.4-]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of 3-hydroxy-spiro[3.4-]oct-2-en-1-one (330 mg, 2.39 mmol)[prepared according to the method of Wasserman, H. H. et al J. Org.Chem, 38, 1451-1455, (1973)] and the free base of Intermediate 27 (911mg, 2.39 mmol), in DCM (5 ml), was stirred at rt for 48 h. The volatileswere removed in vacuo and the residue chromatographed (SiO₂, EtOAc) togive the title compound as a white solid (1.03 g, 2.05 mmol, 86%). δH(CDCl₃, 300K) 8.97 (1H, s), 8.41 (2H, s), 7.51 (2H, d, J 8.5 Hz), 7.01(2H, d, J 8.5 Hz), 5.89 (1H, d, J 7.5 Hz), 4.39 (1H, s), 4.21 (3H,obscured m), 3.15 (1H, dd, J 14.0, 5.3 Hz), 3.03 (1H, dd, J 14.0, 5.8Hz), 1.74-1.49 (10H, m), 1.27 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 502.0(MH⁺).

EXAMPLE 103(2S)-2-[(3-Oxo-spiro[3.4-]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 102 (150 mg, 0.30 mmol) withlithium hydroxide (30 mg, 0.67 mmol), according to the method of Example2, gave the title compound (112 mg, 0.23 mol, 79%). δH (DMSO d⁶, 390K)13.08 (1H, s), 10.87 (1H, s), 8.79 (2H, s), 8.39 (1H, d, J 8.5 Hz), 7.57(2H, d, J 8.2 Hz), 7.26 (2H, d, J 8.2 Hz), 4.39 (1H, s), 4.14 (1H, m),3.16 (1H, dd, J 13.8, 4.7 Hz), 2.98 (1H, dd, J 13.8, 9.4 Hz), 1.73-1.58(10H, m); m/z (ES⁺, 70V) 473.9 (MH⁺).

EXAMPLE 104 Ethyl(2S)-2-[(2-chloro-3-oxo-spiro[3.4-]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared from the compound of Example 102 (1.25 g, 2.49 mmol) andN-chloro succinimide (333 mg, 2.7 mmol), according to the method ofExample 61, to give the title compound as a white powder (1.13 g, 2.1mmol, 84%). δH (DMSO d⁶, 390K) 10.41 (1H, s), 8.68 (2H, s), 8.33 (1H, d,J 5.9 Hz), 7.57 (2H, m), 7.27 (2H, m), 4.66 (1H, m), 4.21 (2H, q, J 7.1Hz), 3.26 (1H, dd, J 14.1, 5.3 Hz), 3.11 (1H, dd, J 14.1, 9.0 Hz),1.98-1.58 (10H, m), 1.23 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 535.9 (MH⁺).

EXAMPLE 105(2S)-2-[(2-Chloro-3-oxo-spiro[3.4-]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 104 (1.10 g, 2.05 mmol) withlithium hydroxide (100 mg, 2.2 mmol), according to the method of Example2, gave the title compound (976 mg, 1.92 mol, 94%). δH (DMSO d⁶, 390K)10.41 (1H, s), 8.69 (2H, s), 8.26 (1H, s), 7.57 (2H, d, J 6.2 Hz), 7.28(2H, d, J 6.2 Hz), 4.61 (1H, m), 3.26 (1H, dd, J 14.1, 5.0 Hz), 3.08(1H, dd, J 14.1, 9.1 Hz), 1.92-1.60 (10H, m); m/z (ES⁺, 70V) 509.9(MH⁺).

EXAMPLE 106 Ethyl(2S)-2-[(2-bromo-3-oxo-spiro[3.4]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of the compound of Example 102 (1.25 g, 2.49 mmol) in THF (25ml) at rt was treated with N-bromo succinimide (443 mg, 2.49 mmol).After 30 min the reaction was diluted with EtOAc (100 ml), washed withsaturated aqueous sodium hydrogencarbonate solution (50 ml) and theorganic phase separated, dried (MgSO₄) and concentrated in vacuo.Chromatography (SiO₂, EtOAc) gave the title compound as a white powder(1.27 g, 2.18 mmol, 87%). δH (DMSO d⁶, 390K) 10.43 (1H, s), 8.69 (2H,s), 8.42 (1H, d, J 8.9 Hz), 7.58 (2H, d, J 6.7 Hz), 7.29 (2H, d, J 6.7Hz), 4.77 (1H, s), 4.22 (2H, q, J 7.1 Hz), 3.26 (1H, dd, J 14.1, 5.4Hz), 3.12 (1H, dd, J 14.1, 9.0 Hz), 1.98-1.62 (8H, m), 1.25 (3H, t, J7.1 Hz); m/z (ES⁺, 70V) 582.0 (MH⁺).

EXAMPLE 107(2S)-2-[(2-Bromo-3-oxo-spiro[3.4-]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 106 (900 mg, 1.54 mmol) withlithium hydroxide (100 mg, 2.2 mmol), according to the method of Example2, gave the title compound (721 mg, 1.3 mmol, 84%). δH (DMSO d⁶, 390K)10.39 (1H, s), 8.68 (2H, s), 8.12 (1H, brs), 7.54 (2H, d, J 8.2 Hz),7.27 (2H, d, J 8.2 Hz), 4.64 (1H, m), 3.25 (1H, dd, J 14.1, 5.1 Hz),3.11 (1H, dd, J 14.1, 8.6 Hz), 1.92-1.62 (8H, m); m/z (ES⁺, 70V) 553.9(MH⁺).

EXAMPLE 108(2S)-Ethyl-2-[(2-methylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of the compound of Example 27 (1.0 g, 1.94 mmol) in THF (25ml) at rt was treated dropwise with a solution of methanesulfenylchloride in DCM (2.13 ml, 1.0M) [prepared according to the method ofStill, I. W. J., et al. J. Org. Chem., 1982, 47, 560]. After 20 min thereaction was diluted with EtOAc (100 ml) and washed with saturatedaqueous sodium hydrogencarbonate solution (50 ml). The organic phase wasseparated, dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (SiO₂, 60% EtOAc:hexanes) gave the title compound as awhite powder (1.03 g, 1.83 mmol, 94%). δH (DMSO d⁶, 390K) 10.86 (1H, s),8.78 (2H, s), 8.70 (1H, d, J 9.2 Hz), 7.57 (2H, d, J 8.4 Hz), 7.26 (2H,d, J 8.4 Hz), 5.11 (1H, m), 4.18 (2H, q, J 7.1 Hz), 3.20 (1H, dd, J13.9, 4.6 Hz), 3.00 (1H, dd, J 13.9, 9.8 Hz), 1.93 (3H, s), 1.66-1.33(10H, m), 1.21 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 562.1 (MH⁺).

EXAMPLE 109(2S)-2-[(2-Methylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 108 (600 mg, 1.07 mmol) withlithium hydroxide (100 mg, 2.2 mmol), according to the method of Example2, gave the title compound as a white powder (421 mg, 0.79 mmol, 73%).δH (DMSO d⁶, 390K) 10.84 (1H, s), 8.77 (2H, s), 8.44 (1H, d, J 8.8 Hz),7.54 (2H, d, J 8.4 Hz), 7.23 (2H, d, J 8.4 Hz), 4.90 (1H, m), 3.19 (1H,dd, J 13.7, 4.4 Hz), 2.98 (1H, dd, J 13.7, 9.1 Hz), 1.93 (3H, s),1.79-1.54 (8H, m), 1.36-1.22 (2H, m); m/z (ES⁺, 70V) 534.0 (MH⁺).

EXAMPLE 110(2S)-Ethyl-2-[(2-fluoro-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of the compound of Example 27 (2.02 g, 3.91 mmol) in THF (55ml) was treated with Selectfluor™ reagent (1.38 g, 3.89 mmol) and heatedto 70°. After 48 h the reaction was diluted with EtOAc (300 ml) andwashed with saturated aqueous sodium hydrogencarbonate solution (50 ml).The organic phase was dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (SiO₂, 60% EtOAc:hexanes) gave the title compound as awhite powder (1.87 g, 3.50 mmol, 89%). δH (DMSO d⁶, 390K) 10.89 (1H, s),8.81 (2H, s), 8.47 (1H, d, J 8.7 Hz), 7.59 (12H, d, J 8.5 Hz), 7.27 (2H,d, J 8.5 Hz), 4.26 (1H, m), 4.19 (2H, q, J 7.1 Hz), 3.21 (1H, dd, J13.8, 4.9 Hz), 2.98 (1H, dd, J 13.8, 9.8 Hz), 1.70-1.38 (10H, m), 1.22(3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 534.1 (MH⁺).

EXAMPLE 111(2S)-2-(2-Fluoro-3-oxo-spiro[3.5]non-1-en-1-ylamino)3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 110 (273 mg, 0.51 mmol) withlithium hydroxide (60 mg, 1.3 mmol), according to the method of Example2, gave the title compound as a white powder (197 mg, 0.39 mmol, 76%).δH (DMSO d⁶, 390K) 10.87 (1H, s), 8.80 (2H, s), 8.30 (1H, d, J 8.7 Hz),7.58 (2H, d, J 8.2 Hz), 7.25 (2H, d, J 8.2 Hz), 4.15 (1H, m), 3.19 (1H,dd, J 13.8, 4.5 Hz), 2.96 (1H, dd, J 13.8, 9.5 Hz), 1.92-1.49 (8H, m),1.37-1.16 (2H, m); m/z (ES⁺, 70V) 506.0 (MH⁺).

EXAMPLE 112(2S)-2-[(2-Fluoro-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

A mixture of the compound of Example 38 (1.0 g, 1.93 mmol) andSelectfluor™ reagent (1.0 g, 2.8 mmol) in THF (25 ml) was heated toreflux for 72 h. The crude reaction was then diluted with EtOAc (100 ml)and washed with saturated aqueous sodium hydrogencarbonate solution (50ml). The organic phase was dried (MgSO₄), filtered and concentrated invacuo to give a gum. This was then redissolved in THF (20 ml) andtreated with lithium hydroxide (80 mg, 1.78 mmol) and water (1 ml) andstirred for 24 h at rt. Acidification with a few drops of AcOH followedby concentration in vacuo and chromatography (SiO₂, 10:90:3:2MeOH:DCM:AcOH:H2O) gave the title compound as a white powder (561 mg,1.1 mmol, 57%). δH (DMSO d⁶, 390K) 10.89 (1H, s), 8.80 (2H, s), 8.58(1H, d, J 8.8 Hz), 7.59 (2H, d, J 8.4 Hz), 7.27 (2H, d, J 8.4 Hz), 4.23(1H, m), 3.76 (2H, m), 3.60 (2H, m), 3.23 (1H, dd, J 13.9, 4.4 Hz), 2.96(1H, dd, J 13.9, 9.8 Hz), 1.98-1.93 (2H, m), 1.47 (1H, m), 1.30 (1H, m);m/z (ES⁺, 70V) 508.0 (MH⁺).

EXAMPLE 113(2S)-2-(2-Fluoro-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Prepared from the compound of Example 5 (1.25 g, 2.49 mmol),Selectfluor™ reagent (1.0 g, 2.8 mmol) and lithium hydroxide (80 mg, 1.8mmol), according to the methods of Examples 61 and 2, to give the titlecompound as a white powder (1.13 g, 2.1 mmol, 84%). δH (DMSO d⁶, 390K)10.88 (1H, s), 8.80 (2H, s), 8.65 (1H, d, J 8.7 Hz), 7.60 (2H, d, J 8.2Hz), 7.27 (2H, d, J 8.2 Hz), 4.25 (1H, m), 3.22 (1H, dd, J 13.9, 4.5Hz), 2.98 (1H, dd, J 13.9, 9.3 Hz), 1.11 (3H, s), 1.03 (3H, s); m/z(ES⁺, 70V) 466.0 (MH⁺).

EXAMPLE 114(2S)-2-[(4,4-Dimethyl-2-methylsulfanyl-3-oxo-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

A solution of the compound of Example 5 (700 mg, 1.47 mmol) in THF (15ml) was treated at rt with a 1.0M solution of methanesulfenyl chloridein DCM (1.5 ml, 1.5 mmol). After 30 min the reaction was partitionedbetween EtOAc (50 ml) and saturated aqueous sodium hydrogencarbonatesolution (25 ml). Separation of the organic phase, followed by drying(MgSO₄), filtration and concentration in vacuo gave a solid which wasapprox. 90% pure. The crude solid was redissolved in THF (20 ml) andtreated with lithium hydroxide (60 mg, 1.3 mmol) and water (1 ml) andstirred at rt for 24 h. The reaction was acidified with a few drops ofAcOH and concentrated in vacuo. Chromatography (SiO₂, 10:90:3:2MeOH:DCM:AcOH:H2O) gave the title compound as a white powder (289 mg,0.59 mmol, 40%). δH (DMSO d⁶, 390K) 10.85 (1H, s), 8.87 (1H, d, J 9.2Hz), 8.80 (2H, s), 7.59 (2H, d, J 8.0 Hz), 7.29 (2H, d, J 8.0 Hz), 5.04(1H, m), 2.25 (1H, dd, J 13.5, 3.5 Hz), 3.00 (1H, dd, J 13.5, 9.8 Hz),2.00 (3H, s), 1.11 (3H, s), 1.02 (3H, s); m/z (ES⁺, 70V) 493.9 (MH⁺).

EXAMPLE 115(2S)-2-[(2-Isopropylsulfanyl-4,4-dimethyl-3-oxo-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Was prepared in two steps from the compound of Example 5 (700 mg, 1.47mmol), a 1.0M solution of isopropyl sulfenyl chloride in DCM (1.5 ml,1.5 mmol) and lithium hydroxide (80 mg, 1.8 mmol), according to themethod of Example 114, to give the title compound as a pale yellowpowder (305 mg, 0.58 mmol, 39%). δH (DMSO d⁶, 390K) 13.24 (1H, s br),10.87 (1H, s), 8.92 (1H, d, J 9.5 Hz), 8.80 (2H, s), 7.58 (2H, d, J 8.4Hz), 7.28 (2H, d, J 8.4 Hz), 5.16 (1H, m), 3.22 (1H, dd, J 13.8, 3.9Hz), 2.97 (1H, dd, J 13.8, 9.7 Hz), 2.67 (1H, m), 1.14 (3H, s),1.06-1.04 (9H, m); m/z (ES⁺, 70V) 522.0 (MH⁺).

EXAMPLE 116 Ethyl(2S)-2-[(2-isopropyisulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}propanoate

A stirred solution of the compound of Example 27 (1.0 g, 1.93 mmol) inTHF (50 ml) at rt was treated dropwise with a 1.0M solution of isopropylsulfenyl chloride in DCM until a yellow colouration of the reactionmixture just persisted. The reaction was then diluted with EtOAc (200ml) and washed with saturated aqueous sodium hydrogencarbonate solution(50 ml). The organic phase was separated, dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (SiO₂, 100% EtOAc) gave the titlecompound as a pale yellow powder (987 mg, 87%). δH (DMSO d⁶, 390K) 10.85(1H, s), 8.79 (2H, s), 8.73 (1H, d, J 9.5 Hz), 7.56 (2H, d, J 8.5 Hz),7.25 (2H, d, J 8.5 Hz), 5.20 (1H, m), 4.17 (2H, q, J 7.1 Hz), 3.18 (1H,dd, J 13.8, 4.3 Hz), 2.97 (1H, dd, J 13.8, 10.2 Hz), 2.65 (1H, m),1.73-1.57 (8H, m), 1.36-1.33 (1H, m), 1.21 (3H, t, J 7.1 Hz), 1.17-1.14(1H, m), 1.02 (6H, d, J 6.6 Hz); m/z (ES⁺, 70V) 590.0 (MH⁺).

EXAMPLE 117(2S)-2-[(2-Isopropyisulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 116 (400 mg, 0.68 mmol) withlithium hydroxide (100 mg, 2.2 mmol), according to the method of Example2, gave the title compound as a white powder (333 mg, 0.59 mmol, 89%).δH (DMSO d⁶, 390K) 10.84 (1H, s), 8.78 (2H, s), 8.62 (1H, d, J 9.4 Hz),7.55 (2H, d, J 8.1 Hz), 7.25 (1H, d, J 8.1 Hz), 5.12 (1H, m), 3.20 (1H,dd, J 13.7, 3.6 Hz), 2.94 (1H, dd, J 13.7, 10.2 Hz), 2.62 (1H, m),1.91-1.64 (8H, m), 1.59-1.56 (1H, m), 1.36-1.33 (1H, m), 1.02 (6H, d, J6.6 Hz); m/z (ES⁺, 70V) 562.0 (MH⁺).

EXAMPLE 118 Ethyl(2S)-2-[(2-isopropylsulfanyl-4,4-dimethyl-3-oxo-cyclobut-1-enyl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoate

A solution of 3-hydroxy-4,4-dimethyl-2-cyclobutenone (333 mg, 2.97 mmol)and Intermediate 12 (1.0 g, 2.98 mmol) in THF (25 ml), was stirred at rtfor 48 h. The volatiles were removed in vacuo and the residuechromatographed (SiO₂, EtOAc) affording 970 mg of the coupled product ofapprox 90% purity. This intermediate was redissolved in THF (35 ml) andtreated with a 1.0M solution of isopropyl sulfenyl chloride in DCM (3.0ml, 3.0 mmol) at rt. After 60 min the reaction was diluted with EtOAc(100 ml) and washed with saturated aqueous sodium carbonate solution (50ml), the organic phase was dried (MgSO₄), filtered and concentrated invacuo. Chromatography (SiO₂, EtOAc) gave the title compound as a whitepowder (817 mg, 1.62 mmol, 54%). δH (DMSO d⁶, 390K) 9.83 (1H, s), 9.52(1H, s), 9.01 (1H, d, J 9.4 Hz), 8.65 (1H, d, J 5.7 Hz), 8.16 (1H, d, J5.7 Hz), 7.81 (2H, d, J 8.5 Hz), 7.68 (1H, d, J 5.7 Hz), 7.23 (2H, d, J8.5 Hz), 7.13 (1H, d, J 5.7 Hz), 5.24 (1H, m), 4.19 (2H, q, J 7.1 Hz),3.20 (1H, dd, J 13.8, 4.5 Hz), 2.97 (1H, dd, J 13.8, 10.0 Hz), 2.76 (1H,m), 1.22 (3H, t, J 7.1 Hz), 1.13 (3H, s), 1.05 (6H, d, J 6.7 Hz), 1.04(3H, s); m/z (ES⁺, 70V) 505.2 (MH⁺).

EXAMPLE 119(2S)-2-[(2-Isopropylsulfanyl-4,4-dimethyl-3-oxo-cyclobut-1-enyl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoate

Hydrolysis of the compound of Example 118 (400 mg, 0.79 mmol) withlithium hydroxide (100 mg, 2.2 mmol), according to the method of Example2, gave the title compound as a white powder (231 mg, 0.49 mmol, 62%).δH (DMSO d⁶, 390K) 9.83 (1H, s), 9.51 (1H, s), 8.89 (1H, d, J 9.5 Hz),8.65 (1H, d, J 5.6 Hz), 8.15 (1H, d, J 5.7 Hz), 7.78 (2H, d, J 8.5 Hz),7.22 (2H, d, J 8.5 Hz), 7.11 (1H, d, J 5.7 Hz), 5.16 (1H, m), 3.21 (1H,dd, J 13.8, 4.1 Hz), 2.94 (1H, dd, J 13.8, 6.7 Hz), 2.75 (1H, m), 1.13(3H, s), 1.06 (6H, d, J 6.6 Hz), 1.03 (3H, s); m/z (ES⁺, 70V) 477.1(MH⁺).

EXAMPLE 120 Ethyl(2S)-2-[(2-isopropyisulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoate

Was prepared in two steps from Intermediate 12 (1.0 g, 2.98 mmol),1-keto-3-hydroxyspiro[3,5]-non-2-ene (452 mg, 2.97 mmol) [preparedaccording to the method of Wasserman, H. H. et al, J. Org. Chem., 38,1451-1455 (1973)] and a 1.0M solution of isopropyl sulfenyl chloride inDCM (3.5 ml, 3.5 mmol) according to the method of Example 118 to givethe title compound as a yellow powder (931 mg, 1.71 mmol, 58%). (DMSOd⁶, 390K) 9.89 (1H, s), 9.58 (1H, s), 8.82 (1H, d, J 9.4 Hz), 8.71 (1H,d, J 5.6 Hz), 8.21 (1H, d, J 5.6 Hz), 7.85 (2H, d, J 8.3 Hz), 7.74 (1H,d, J 5.6 Hz), 7.28 (2H, d, J 8.3 Hz), 7.18 (1H, d, J 5.6 Hz), 5.31 (1H,m), 4.24 (2H, q, J 7.1 Hz), 3.24 (1H, dd, J 13.7, 4.1 Hz), 3.03 (1H, dd,J 13.7, 10.3 Hz), 2.80 (1H, m), 1.80-1.71 (8H, m), 1.46-1.43 (1H, m),1.28 (3H, t, J 7.1 Hz), 1.24-1.21 (1H, m), 1.11 (6H, d, J 6.5 Hz); m/z(ES⁺, 70V) 545.2 (MH⁺).

EXAMPLE 121(2S)-2-[(2-lsopropyisulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoicacid

Hydrolysis of the compound of Example 120 (900 mg, 1.62 mmol) withlithium hydroxide (150 mg, 3.3 mmol), according to the method of Example2, gave the title compound as a bright yellow powder (790 mg, 1.53 mmol,94%). δH (DMSO d⁶, 390K) 9.83 (1H, s), 9.51 (1H, s), 8.67 (1H, d, J 5.6Hz), 8.65 (1H, d, J 5.6 Hz), 8.15 (1H, d, J 5.7 Hz), 7.77 (2H, d, J 8.4Hz), 7.68 (1H, d, J 5.7 Hz), 7.23 (2H, d, J 8.4 Hz), 7.12 (1H, J 5.7Hz), 5.20 (1H, m), 3.22 (1H, dd, J 13.8, 3.9 Hz), 2.94 (1H, dd, J 13.8,10.4 Hz), 1.79-1.66 (8H, m), 1.40-1.35 (1H, m), 1.20-1.15 (1H, m), 1.05(3H, d, J 6.3 Hz), 1.03 (3H, d, J 6.3 Hz); m/z (ES⁺, 70V) 517.2 (MH⁺).

EXAMPLE 122 Ethyl(2S)-2-[(2-isopropyisulfanyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoate

Was prepared in two steps from Intermediate 12 (1.96 g, 5.8 mmol),7-oxaspiro[3.5]nonane-1,3-dione (1.0 g, 6.5 mmol) [prepared according tothe method of Wasserman, H. H. et al, J. Org. Chem., 38, 1451-1455(1973)] and a 1.0M solution of isopropyl sulfenyl chloride in DCM (5.4ml, 5.4 mmol) according to the method of 118 to give the title compoundas a yellow powder (1.15 g, 2.1 mmol, 36%). δH (DMSO d⁶, 390K) 9.83 (1H,s), 9.52 (1H, s), 8.94 (1H, d, J 9.5 Hz), 8.65 (1H, d, J 5.6 Hz), 8.15(1H, d, J 5.7 Hz), 7.78 (2H, d, J 8.5 Hz), 7.68 (1H, d, J 5.6 Hz), 7.23(2H, d, J 8.5 Hz), 7.12 (1H, d, J 5.7 Hz), 5.26 (1H, m), 4.19 (2H, q, J7.1 Hz), 3.81-3.76 (2H, m), 3.64-3.55 (2H, m), 3.20 (1H, dd, J 13.8, 4.3Hz), 2.96 (1H, dd, J 13.8, 10.3 Hz), 2.81-2.74 (1H, m), 2.06-1.93 (2H,m), 1.50-1.47 (1H, m), 1.32-1.28 (1H, m), 1.23 (3H, t, J 7.1 Hz), 1.07(3H, d, J 6.6 Hz), 1.05 (3H, d, J 6.6 Hz); m/z (ES⁺, 70V) 547.2 (MH⁺).

EXAMPLE 123(2S)-2-[(2-Isopropyisulfanyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoicacid

Hydrolysis of the compound of Example 122 (906 mg, 1.66 mmol) withlithium hydroxide (150 mg, 3.3 mmol), according to the method of Example2, gave the title compound as a pale yellow powder (801 mg, 1.54 mmol,93%). δH (DMSO d⁶, 390K) 9.82 (1H, s), 9.51 (1H, s), 8.86 (1H, d, J 9.5Hz), 8.65 (1H, d, J 5.5 Hz), 8.14 (1H, d, J 5.6 Hz), 7.76 (2H, d, J 8.1Hz), 7.68 (1H, d, J 5.5 Hz), 7.28 (2H, d, J 8.1 Hz), 7.12 (1H, d, J 5.6Hz), 5.24-5.19 (1H, m), 3.78 (2H, m), 3.61 (2H, m), 3.21 (1H, dd, J13.8, 3.5 Hz), 2.91 (1H, dd, J 13.8, 10.7 Hz), 2.77-2.71 (1H, m),2.05-1.91 (2H, m), 1.49-1.46 (1H, m), 1.30-1.26 (1H, m), 1.07 (3H, s),1.03 (3H, s); m/z (ES⁺, 70V) 519.1 (MH⁺).

EXAMPLE 124 Ethyl(2S)-2-[(3-oxo-spiro[3.4-]octa-1,6-dien-1-yl)amino]-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of Intermediate 47 (1.0 g, 7.3 mmol) and the free base ofIntermediate 27 (2.48 g, 7.3 mmol), in DCM (25 ml), was stirred at roomtemperature for 48 h. The volatiles were removed in vacuo and theresidue chromatographed (SiO₂, EtOAc) to give the title compound as awhite solid (2.14 g, 4.28 mmol, 59%). δH (CDCl₃, 300K) 9.02 (1H, s),8.38 (2H, s), 7.49 (2H, d, 8.5 Hz), 7.00 (2H, d, J 8.5 Hz), 6.03 (1H, d,J 7.8 Hz), 5.54 (2H, s), 4.41 (1H, s), 4.21 (2H, q, J 7.1 Hz), 4.20 (1H,m), 3.15 (1H, dd, J 14.0, 5.2 Hz), 3.03 (1H, dd, J 14.0, 6.1 Hz),1.56-1.51 (2H, m), 2.38-2.34 (2H, m), 1.18 (3H, t, J 7.1 Hz); m/z (ES⁺,70V) 500.0 (MH⁺).

EXAMPLE 125(2S)-2-[(3-Oxo-spiro[3.4-]octa-1.6-dien-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 124 (970 mg, 1.94 mmol) withlithium hydroxide (100 mg, 2.2 mmol), according to the method of Example2, gave the title compound (896 mg, 1.90 mol, 98%). δH (DMSO d⁶, 390K)10.87 (1H, s), 8.80 (2H, s), 8.45 (1H, d, J 8.4 Hz), 7.57 (2H, d, J 8.5Hz), 7.27 (2H, d, J 8.5 Hz), 5.63 (2H, s), 4.41 (1H, s), 4.11 (1H, m),3.17 (1H, dd, J 13.9, 4.8 Hz), 2.98 (1H, dd, J 13.9, 9.3 Hz), 2.46-2.42(2H, m), 2.36-2.25 (2H, m); m/z (ES⁺, 70V) 471.9 (MH⁺).

EXAMPLE 126 Ethyl(2S)-2-[(2-bromo-3-oxo-spiro[3.4-]octa-1,6-dien-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Bromination of the compound of Example 124 (206 mg, 0.41 mmol) withN-bromo succinimide (75 mg, 0.57 mmol), according to the method ofExample 36 afforded the title compound as a white solid (116 mg, 0.20mmol, 50%). δH (DMSO d⁶, 390K) 10.36 (1H, s), 8.67 (2H, s), 8.45 (1H, d,J 9.0 Hz), 7.58 (2H, d, J 8.5 Hz), 7.28 (2H, d, J 8.5 Hz), 5.67-5.63(2H, m), 4.50 (1H, s br), 4.23 (2H, q, J 7.1 Hz), 3.28 (1H, dd, J 14.1,6.3 Hz), 3.15 (1H, dd, J 14.1, 9.0 Hz), 2.52-2.42 (4H, m), 1.28 (3H, t,J 7.1 Hz); m/z (ES⁺, 70V) 579.0 (MH⁺).

EXAMPLE 127(2S)-2-[(2-Bromo-3-oxo-spiro[3.4-]octa-1.6-dien-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 126 (190 mg, 0.33 mmol) withlithium hydroxide (60 mg, 1.3 mmol), according to the method of Example2, gave the title compound (162 mg, 0.29 mol, 88%). δH (DMSO d⁶, 390K)10.89 (1H, s), 9.09-9.04 (1H, m), 8.81 (2H, s), 7.62 (2H, d, J 8.5 Hz),7.29 (2H, d, J 8.5 Hz), 5.69-5.60 (2H, m), 4.72 (1H, m), 3.03 (1H, dd, J14.1, 9.0 Hz), 2.98 (1H, dd, J 14.1, 6.7 Hz), 2.62-2.20 (4H, m); m/z(ES⁺, 70V) 551.8 (MH⁺).

EXAMPLE 128 Ethyl(2S)-2-[(4.4-dimethyl-3-oxo-2-pentafluorophenylsulfanyl-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Was prepared from the compound of Example 5 (500 mg, 1.06 mmol) andpentafluorophenyl sulphenyl chloride (273 mg, 1.17 mmol), according tothe method of Example 93 to give the title compound as a white powder(459 mg, 0.68 mmol, 64%). δH (CDCl₃, 300K); 8.41 (2H, s), 7.41 (2H, d, J8.4 Hz), 6.99 (2H, d, J 8.4 Hz), 5.98 (1H, d, J 8,8 Hz), 5.18-5.12 (1H,m), 4.12 (2H, q, J 7.1 Hz), 3.17 (1H, dd, J 14.1, 5.6 Hz), 3.10 (1H, dd,J 14.1, 5.7 Hz), 1.18 (3H, t, J 7.1 Hz), 1.03 (3H, s), 1.01 (3H, s); m/z(ES⁺, 70V) 673.9 (MH⁺).

EXAMPLE 129(2S)-2-[(4,4-Dimethyl-3-oxo-2-pentafluorophenylsulfanyl-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

Hydrolysis of the compound of Example 128 (440 mg, 0.65 mmol) withlithium hydroxide (60 mg, 1.4 mmol), according to the method of Example2, gave the title compound (372 mg, 0.57 mmol, 88%) as a white powder.δH (DMSO d⁶, 390K) 13.75 (1H, br s), 10.62 (1H, s), 9.16 (1H, d, J 9.5Hz), 8.54 (2H, s), 7.30 (2H, d, J 8.5 Hz), 6.97 (2H, d, J 8.5 Hz),4.83-4.77 (1H, m), 3.0 (1H, dd, J 14.0, 4.1 Hz), 2.71 (1H, dd, J 14.0,10.0 Hz), 0.83 (3H, s), 0.75 (3H, s); m/z (ES⁺, 70V) 645.9 (MH⁺).

EXAMPLE 130 Ethyl(2S)-2-(4,4-dimethyl-3-oxo-2-pyrazin-2-yl-cyclobut-1-enylamino)-3-{4[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution containing vinyl iodide (500 mg, 0.81 mmol), palladiumdichloride (14 mg), triphenyl arsine (101 mg), 2-tributylstannyl1,4-pyridazine (307 mg), and copper iodide (15 mg) in DMF was heated to950 for 3 h. The reaction was then diluted with saturated aqueous sodiumhydrogencarbonate solution (50 ml) and EtOAc (100 ml). The organic phasewas removed, dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (SiO₂, 50% EtOAc:hexanes) gave the title compound (127mg, 0.23 mmol, 28%). δH (CDCl₃, 300K) 9.51 (1H, s), 8.72 (1H, s), 8.26(1H, m), 8.11 (1H, d, J 2.7 Hz), 7.97 (1H, d, J 10.9 Hz), 7.54 (2H, d, J8.5 Hz), 4.244.15 (3H, m), 3.18 (1H, dd, J 13.9, 5.2 Hz), 3.11 (1H, dd,J 13.9, 4.6 Hz), 1.23 (3H, t, J 7.1 Hz), 1.22 (3H, s), 0.98 (3H, s); m/z(ES⁺, 70V) 554.1 (MH⁺).

EXAMPLE 131(2S)-2-[(4,4-Dimethyl-3-oxo-2-pyrazin-2-yl-cyclobut-1-enyl)amino]-3-{4[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Hydrolysis of the compound of Example 130 (50 mg, 0.09 mmol) withlithium hydroxide (10 mg, 0.23 mmol), according to the method of Example2, gave the title compound (33 mg, 0.064 mmol, 71%) as a white powder.LCMS indicates the presence of two separate atropisomers. δH (DMSO d⁶,390K, 1 atropisomer) 10.49 (1H, s), 8.90 (1H, br m), 8.69 (2H, s), 8.42(1H, br m), 8.21 (1H, br m), 7.43 (2H, d, J 8.3 Hz), 7.21 (2H, d, J 8.3Hz), 5.95 (1H, br s), 4.20 (1H, m), 3.27-3.22 (1H, m), 3.06 (1H, m),1.28 (3H, s), 1.19 (3H, s); m/z (ES⁺, 70V) 526.0 (MH⁺).

EXAMPLE 132 Ethyl(2S)-2-[(4-methyl-3-oxo-4-phenyl-cyclobut-1-enyl)amino]-3-{4-[(3,5dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared from Intermediate 49 (300 mg, 1.72 mmol) and the free base ofIntermediate 27 (400 mg, 1.04 mmol), in a similar manner to the compoundof Example 11, to give the title compound as a white powder (329 mg,0.61 mmol, 59%) as an approx. 1:1 mixture of diastereomers. δH (CDCl₃,300K) 10.95 (1H, s), 10.88 (1H, s), 8.89 (1H, d, J 8.6 Hz), 8.81 (2H,s), 8.80 (2H, s), 8.74 (1H, d, J 8.8 Hz), 7.63 (2H, d, J 8.5 Hz), 7.59(2H, d, J 8.5 Hz), 7.34-7.10 (5H, m), 6.89 (2H, d, J 8.5 Hz), 6.85 (2H,d, J 8.5 Hz), 4.71 and 4.66 (1H, s), 4.48-4.42 and 4.38-4.33 (1H, m),4.21 (2H, t, J 7.1 Hz), 3.31-3.01 (2H, m), 1.52 and 1.42 (3H, s), 1.25(3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 537.9 (MH⁺).

EXAMPLE 133 Ethyl(2S)-2-[(4-methyl-3-oxo-4-phenyl-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

The compound of Example 132 (100 mg, 0.18 mmol) was hydrolysed in asimilar manner to the method of Example 2 to give the title compound asa fine white solid (79 mg, 0.15 mmol, 86%) as an approx. 1:1 mixture ofdiastereomers. δH (DMSO d⁶, 360K) 10.95 and 10.88 (1H, s), 8.82 and 8.81(2H, s), 8.65 (1H, d, J 8.7 Hz), 7.63 and 7.59 (2H, d, J 8.5 Hz),7.23-7.10 (5H, m), 6.88 and 6.85 (2H, d, J 8.5 Hz), 4.70 and 4.63 (1H,s), 4.36-4.25 and 4.25-4.22 (1H, m), 3.31-3.00 (2H, m), 1.41 and 1.25(3H, s); m/z (ES⁺, 70V) 509.9 (MH⁺).

EXAMPLE 134 Ethyl(2S)-2-[(7-acetyl-2-bromo-3-oxo-7-aza-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of the compound of Example 51 (100 mg, 0.18 mmol) in THF (10ml) at rt was treated with N-bromo succinimide (32 mg, 0.19 mmol). After30 min the reaction was diluted with EtOAc (50 ml) and saturated aqueoussodium hydrogencarbonate solution (30 ml), the organic phase separatedand dried (MgSO₄), filtered and concentrated in vacuo. Chromatography(SiO₂, EtOAc) gave the title compound as a white powder (79 mg, 0.12mmol, 67%). δH (CDCl₃, 300K) 9.54 (1H, s), 8.65 (1H, d, J 9.4 Hz), 8.19(2H, s), 7.49 (2H, d, J 8.4 Hz), 7.07 (2H, d, J 8.4 Hz), 4.91-4.81 (1H,m), 4.11 (2H, q, J 7.1 Hz), 3.49-3.44 (1H, m), 3.25-2.66 (5H, m), 1.89(3H, s), 1.86-1.25 (4H, m), 1.18 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 639.0(MH⁺).

EXAMPLE 135(2S)-2-[(7-Acetyl-2-bromo-3-oxo-7-aza-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 134 (50 mg, 0.078 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white powder (21 mg, 0.034 mmol, 44%). δH (DMSO d⁶, 390K) 10.38 (1H,s), 8.96 (2H, s), 7.57 (2H, s br), 7.28 (2H, d, J 7.9 Hz), 4.78 (1H, m),3.99-3.96 (2H, m), 3.30-3.06 (4H, m), 2.00 (3H, s), 1.94-1.84 (2H, m),1.48-1.21 (2H, m); m/z (ES⁺, 70V) 610.9 (MH⁺).

EXAMPLE 136 Ethyl (2S)-2-(2-benzyl-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A solution of the free acid of Intermediate 27 (0.82 g, 2.1 mmol) andIntermediate 72 (0.48 g, 2.3 mmol, 1.1 eq.) in nitromethane (8 ml) wastreated with acetic acid (1 drop). The resulting mixture was heated at100° for 2 h. and then partitioned between EtOAc (50 ml) and water (25ml), the organics were separated, washed with water (25 ml), Na₂CO₃ (25ml, sat. aq.), brine (25 ml), dried (Na₂SO₄), filtered and concentratedin vacuo to give a crude foam. This was purified by columnchromatography (SiO₂, gradient elution 1:1, hexane:EtOAc to EtOAc) togive the title compound as a white solid (0.71 g, 59%). δH (DMSO d⁶, 400MHz) 10.87 (1H, s), 8.81 (2H, s), 8.38 (1H, d, J 9.3 Hz), 7.53 (2H, d, J8.4 Hz), 7.33 (2H, m), 7.15 (2H, m), 7.09 (2H, d, J 8.5 Hz), 7.03 (2H,d, J 7.2 Hz), 4.15 (1H, m), 4.04 (2H, dq, J 7.1, 1.6 Hz), 3.19 (2H, m),3.04 (1H, dd, J 13.8, 5.0 Hz), 2.89 (1H. dd, J 9.5, 4.8 Hz), 1.02-1.26(8H, m); m/z (ES⁺, 70V) 566 (MH⁺).

EXAMPLE 137(2S)-2-(2-Benzyl-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

To a solution of the compound of Example 136 (210 mg, 0.4 mmol) in THF(2 ml) was added a solution of lithium hydroxide hydrate (25 mg, 0.6mmol, 1.5 eq) in water (1 ml). The solution was stirred at roomtemperature for 3 h. The reaction mixture was concentrated in vacuo andthe residue redissolved in water (15 ml) and washed with diethyl ether(10 ml). The aqueous was concentrated to approx. 5 ml and taken to pH 4with HCl (2M, aq.). The resulting solid was filtered, washed on thesinter with water, diethyl ether and dried in vacuo to give the titlecompound as a white solid (170 mg, 85%). δH (400 MHz, DMSO d⁶, 380K)10.42 (1H, br), 8.70 (2H, s), 7.64 (1H, d, J 9.4 Hz), 7.52 (2H, d, J 6.6Hz), 7.25 (2H, m), 7.13-7.18 (5H, m), 4.13 (1H, m), 3.26 (2H, d, J 2.9Hz), 3.13 (1H, dd, J 14.0, 4.9 Hz), 2.97 (1H, dd, J 14.0, 9.0 Hz), 1.12(3H, s), 1.09 (3H, d, J 15.7 Hz); m/z (ES⁺, 70V) 538 (MH⁺).

EXAMPLE 138 Isopropyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

To a solution of the compound of Example 32 (0.5 g, 0.9 mmol) in DMF (5ml) was added EDC (185 mg, 1.1 eq), HOBT (135 mg, 1.1 eq) andisopropanol (0.5 ml). The mixture was stirred at room temperature for 48h. then partitioned between EtOAc (100 ml) and water (50 ml). Theaqueous was separated and the organics washed with water (5×30 ml),brine (30 ml), dried (Na₂SO₄), filtered and concentrated in vacuo togive a crude solid. The crude was triturated with diethyl ether to givethe title compound as a white powder (0.35 g, 65%) δH (300 MHz, DMSO d⁶)10.69 (1H, br), 8.68 (1H, d, J 9.1 Hz), 8.60 (2H, s), 7.39 (2H, d, J 8.5Hz), 7.08 (2H, d J 8.5 Hz), 4.78 (1H, sep, J 6.3 Hz), 4.53 (1H, m), 3.01(1H, dd, J 13.8, 4.9 Hz), 2.83 (1H, dd, J 13.9, 9.5 Hz), 1.36-1.60 (9H,m), 1.19 (1H, d, J 12.7 Hz), 0.98-1.05 (6H, dd); m/z (ES⁺, 70V) 608(MH⁺).

EXAMPLE 139 1-Methyl-piperidin-4-yl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Using a similar procedure to that for the preparation the compound ofExample 138 from the compound of Example 32 (0.5 g, 0.89 mmol), EDC (185mg, 1.1 eq), HOBT (135 mg, 1.1 eq), 4-hydroxy-1-methylpiperidine (0.5ml) and DMF (2 ml) was prepared the title compound (0.21 g, 36%). δH(300 MHz, DMSO d⁶) 11.01 (1H, br), 9.01 (1H, d, J 9.4 Hz), 8.92 (2H, s),7.71 (2H, d, J 8.5 Hz), 7.40 (2H, d, J 8.5 Hz), 4.90 (1H, br), 3.33 (1H,dd, J 13.8, 4.8 Hz), 3.16 (1H, dd, J 13.8, 9.6 Hz), 2.55 (2H, br), 2.40(2H, br), 2.24 (3H, d, J 8.0 Hz), 1.64-1.95 (12H, m), 1.50 (2H, d, J12.1 Hz), 1.23 (2H, br); m/z (ES⁺, 70V) 664 (MH⁺).

EXAMPLE 140 Cyclopentyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Using a similar procedure to that for the preparation the compound ofExample 138 from the compound of Example 32 (0.5 g, 0.89 mmol, EDC (600mg, 3 eq), HOBT (400 mg, 3 eq), cyclopentanol (0.5 ml) and DMF (5 ml)]was prepared the title compound. δH (400 MHz, DMSO d⁶) 10.88 (1H, s),8.85 (1H, d, J 9.0 Hz), 8.78 (2H, s), 7.58 (2H, d, J 8.5 Hz), 7.26 (2H,d, J 8.5 Hz), 5.15 (1H, m), 4.71 (1H, m), 3.18 (1H, dd, J 13.9, 5.2 Hz),3.02 (1H, dd, J 13.9, 9.5 Hz), 1.17-1.84 (18H, m), 1.14 (1H, m); m/z(ES⁺, 70V) 634 (MH⁺).

EXAMPLE 141 Tetrahydro-furan-3-yl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3(4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Using a similar procedure to that for the preparation the compound ofExample 138 from the compound of Example 32 acid (0.5 g, 0.89 mmol), EDC(600 mg, 3 eq), HOBT (400 mg, 3 eq), (S)-3-hydroxytetrahydrofuran (0.5ml) and DMF (5 ml)] was prepared the title compound. δH (300 MHz, DMSOd⁶) 8.87 (1H. d, J 8.9 Hz), 8.79 (2H, s), 7.58 (2H, d, J 8.4 Hz), 7.27(2H, d, J 8.5 Hz), 5.30 (1H, m), 4.77 (1H, m), 3.72-3.83 (3H, m), 3.65(1H, d, J 10.4 Hz), 3.20 (1H, dd, J 14.0, 5.1 Hz), 3.04 (1H, dd, J 14.0,9.7 Hz), 2.11-2.27 (1H, m), 1.87-1.99 (1H, m), 1.37-1.78 (9H, m),1.07-1.17 (1H, m); m/z (ES⁺, 70V) 636 (MH⁺).

EXAMPLE 142 1-Methyl-pyrrolidin-3-yl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}propanoate

Using a similar procedure to that for the preparation the compound ofExample 138 from the compound of Example 32 (0.5 g, 0.89 mmol), EDC (600mg, 3 eq), HOBT (400 mg, 3 eq), 1-methyl-3-pyrrolidinol (0.6 ml) and DMF(5 ml) was prepared the title compound. δH (400 MHz, DMSO d⁶) 10.88 (1H,s), 8.87 (1H, d, J 9.0 Hz), 8.78 (2H, s), 7.58 (2H, d, J 8.3 Hz), 7.26(2H, d, J 8.5 Hz), 5.13 (1H, m), 4.74 (1H, m), 3.16 (1H, m), 3.04 (1H,m), 2.43-2.73 (2H, m), 2.07-2.26 (2H, m), 1.55-1.75 (11H, m), 1.11 (1H,m). m/z (ES⁺, 70V) 649 (MH⁺).

EXAMPLE 143 Phenyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Using a similar procedure to that for the preparation the compound ofExample 138 from the compound of Example 32 (0.5 g, 0.89 mmol, EDC (500mg, 2.6 eq), HOBT (350 mg, 2.6 eq), phenol (0.5 g) and DMF (5 ml)] wasprepared the title compound (0.1 7 g, 29%). δH (300 MHz, DMSO d⁶) 11.10(1H, br)), 9.24 (1H, d, J 8.8 Hz), 8.98 (2H, s), 7.81 (2H, d, J 8.5 Hz),7.47-7.67 (5H, c), 7.31 (2H, dd, J 8.4, 0.9 Hz), 6.93 (1H, d, J 8.1 Hz),5.20 (1H, br), 3.59 (1H, dd, J 9.3, 6.0 Hz), 3.40 (1H, dd, J 14.0, 9.3Hz), 1.60-1.97 (10H, m); m/z (ES⁺, 70V) 644 (MH⁺).

EXAMPLE 144 Pyridin-4-ylmethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}propanoate

Using a similar procedure to that for the preparation the compound ofExample 138 from the compound of Example 32 (0.60 g, 1.1 mmol), EDC (222mg, 1.1 eq), HOBT (162 mg, 1.1 eq), 4-pyridinemethanol (0.36 g, 3.2mmol) and DMF (5 ml)] was prepared the title compound (0.48 g, 66%). δH(400 MHz, DMSO d⁶, 380K) 10.43 (1H, br), 8.69 (2H, s), 8.57 (2H, d, J6.0 Hz), 8.38 (1H, d, J 8.1 Hz), 7.57 (2H, m), 7.30 (4H, m), 5.26 (2H,s), 4.95 (1H, br), 3.32 (1H, dd, J 14.2, 5.4 Hz), 3.17 (1H, dd, J 14.1,9.1 Hz), 1.46-1.71 (9H, m), 1.21 (1H, br m); m/z (ES⁺, 70V) 657 (MH⁺).

EXAMPLE 145 Methyl(2S)-2-[(3-oxo-7-oxaspiro[3.5]non-1-en-yl)amino]-3-(2,6-dimethoxyr[1,1′-biphenyl]-4-yl)propanoate

Using a similar procedure to that for the preparation the compound ofExample 38 from methyl(2S)-2-amino-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate (2.0 g, 6.3mmol) and 7-oxaspiro[3.5]nonane-1,3-dione (1.1 g, 1.1 eq) in DCM (30 ml)was prepared the title compound as a white foam (2.4 g, 86%). δH (300MHz, DMSO d⁶) 8.53 (1H, d, J 8.7 Hz), 7.20-7.30 (3H, m), 7.08 (2H, d, J8.1 Hz), 6.70 (2H, d, J 8.5 Hz), 4.44 (1H, s), 4.30 (1H, m), 3.72 (3H,s), 3.61 (6H, s), 3.22 (1H, dd, J 13.7, 5.0 Hz), 2.98 (1H, dd, J 13.8,10.1 Hz), 1.74-1.99 (2H, m), 1.48 (1H, d, J 13.6 Hz), 1.31 (1H, d J 13.0Hz); m/z (ES⁺, 70V) 439 (MH⁺).

EXAMPLE 146 Methyl(2S)-2-{[2-(isopropylsulfanyl)-3-oxo-7-oxaspiro[3.5]non-1-en-yl)]amino}-3-(2.6-dimethoxy[1′-biphenyl]-4-yl)propanoate

The title compound was prepared in a similar manner to the compound ofExample 70 from the bromo derivative of the compound of Example 145 (0.5g, 1.1 mmol) as a white foam (0.42 g, 73%). δH (400 MHz, DMSO d⁶) 8.91(1H, d, J 9.4 Hz), 7.29-7.21 (3H, m), 7.09 (2H, d, J 8.2 Hz), 6.70 (2H,d, J 8.4 Hz), 5.32 (1H, br), 3.74-3.80 (5H, m), 3.54-3.64 (8H, m), 3.28(1H, dd, J 16.4, 4.2 Hz), 2.97 (1H, dd, J 13.6, 10.8 Hz), 2.76 (1H, sep,J 6.7 Hz), 1.99 (1H, dt, J 11.5, 4.8 Hz), 1.84 (1H, dt, J 13.0, 4.8 Hz),1.48 (1H, d, J 12.1 Hz), 1.25 (1H, d, J 12.2 Hz), 1.05 (3H, d, J 6.7Hz), 1.02 (3H, d, J 6.7 Hz); mp/z (ES⁺, 70V) 526 (MH⁺).

EXAMPLE 147 Ethyl(2S)-2-[(4,4,-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate

The title compound was prepared in a similar manner to that of thecompound of Example 41 from ethyl(2S)-2-amino-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate (1.5 g, 4.5mol), and 3-hydroxy-4,4-dimethyl-2-cyclobutenone (0.5 g, 4.5 mmol) inDCM (15 ml) as a white foam (1.8 g, 93%). δH (300 MHz, DMSO d⁶) 8.68(1H, d, J 8.6 Hz), 7.22-7.37 (3H, m), 7.18 (2H, d, J 8.3 Hz), 6.78 (2H,d, J 8.4 Hz), 4.46 (1H, s), 4.32 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3.69(6H, s), 3.24 (1H, dd, J 13.8, 5.9 Hz), 3.09 (1H, dd, J 13.8, 9.1 Hz),1.24 (3H, t, J 7.1 Hz), 1.16 (3H, s), 1.08 (3H, s); m/z (ES⁺, 70V) 424(MH⁺).

EXAMPLE 148 Ethyl(2S)-2-{[2-(isopropylsulfanyl)-4,4,-dimethyl-3-oxo-1-cyclobutenyl]amino}-3-(2,6-dimethoxyr[1,1′-biphenyl]-4-yl)propanoate

The title compound was prepared in a similar manner to the compound ofExample 70 as a white foam (0.52 g, 87%). δH (400 MHz, DMSO d⁶, 380K)8.99 (1H, d, J 9.5 Hz), 7.21-7.29 (3H, m), 7.10 (2H, d, J 8.1 Hz), 6.70(2H, d, J 8.4 Hz), 5.29 (1H, m), 4.17 (2H, q, J 7.1 Hz), 3.60 (6H, s),3.23 (1H, dd, J 13.8, 5.0 Hz), 2.99 (1H, dd, J 13.8, 10.4 Hz), 2.79 (1H,sep, J 6.6 Hz), 0.99-1.25 (15H, m). m/z (ES⁺, 70V) 498 (MH⁺).

EXAMPLE 149(2S)-2-{[2-(isopropyisulfanyl)-3-oxo-7-oxaspiro[3.5]non-1-en-yl)]amino}-3-(2.6-dimethoxy[1,1′-biphenyl]-4-yl)propanoic acid

Prepared from the compound of Example 146 (0.25 g, 0.46 mmol) in asimilar manner to that of Example 2 to give the title compound as awhite powder (0.21 g, 89%). δH (400 MHz, DMSO d⁶) 8.80 (1H, d, J 9.5Hz), 7.21-7.28 (3H, m), 7.08 (2H, d, J 8.1 Hz), 6.70 (2H, d, J 8.4 Hz),5.25 (1H, m), 3.76 (2H, m), 3.59 (8H, m), 3.30 (1H), 2.93 (1H, dd, J13.6, 10.9 Hz), 2.76 (1H, sep, J 6.8 Hz), 1.99 (1H, m), 1.86 (1H, m),1.46 (1H, d, J 13.1 Hz), 1.23 (1H, d, J 12.7 Hz), 1.06 (3H, d, J 7.8Hz), 1.03 (3H, d, J 7.8 Hz); m/z (ES⁺, 70V) 512 (MH⁺).

EXAMPLE 150 (2S)2-{[2-(isopropyisulfanyl)-4,4,-dimethyl-3-oxo-1-cyclobutenyl]amino}-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoicacid

Prepared from the compound of Example 148 (0.31 g, 0.64 mmol) in asimilar manner to that of Example 2 to give the title compound as awhite powder (0.13 g, 44%). δH (400 MHz, DMSO d⁶) 8.85 (1H, br d),7.21-7.29 (3H, m), 7.08 (2H, d, J 8.0 Hz), 6.70 (2H, d, J 8.4 Hz), 5.15(1H, br), 3.61 (6H, s), 3.91 (1H, dd, J 13.7, 8.6 Hz), 2.77 (1H, sep),0.98-1.14 (6H, m); m/z (ES⁺, 70V) 470 (MH⁺).

EXAMPLE 151 Ethyl(2S)-2-[(2-cyclohexyl-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

A mixture of the free amine of Intermediate 27 (1000 mg, 2.61 mmol),Intermediate 52 (611 mg, 2.61 mmol) and nitromethane (10 ml) were heatedat reflux for 5 hours. The solvent was removed by evaporation underreduced pressure and the residue chromatographed (SiO₂, 3:2hexane:EtOAc), to afford the title compound as a colorless oil (310 mg,20%). δH (CDCl₃) 8.51 (2H, s), 7.80 (1H, br s), 7.52 (2H, d, J 8.5 Hz),7.07 (2H, d, J 8.5 Hz), 5.15 (1H, d, J 7.6 Hz), 4.32 (1H, m), 4.20 (2H,q, J 7.1 Hz), 3.07 (2H, d, J 5.6 Hz), 1.75-1.40 (20H, m), 1.19 (3H, t, J7.1 Hz).

EXAMPLE 152(2S)-2-[(2-Cyclohexyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}propanoicacid

The compound of Example 151 was hydrolysed by the method of Example 2,giving the title compound (78%). δH (DMSO d⁶) 10.84 (1H, br s), 8.78(2H, s), 7.60 (1H, s), 7.56 (2H, d, J 8.2 Hz), 7.25 (2H, d, J 7.9 Hz),4.06 (1H, m), 3.12 (1H, dd, J 13.6, 3.9 Hz), 2.92 (1H, dd, J 13.4, 9.8Hz), 1.80-1.00 (21H, m); m/z (ES⁺, 70V) 570.1 (MH⁺)

EXAMPLE 153 Ethyl(2S)-3-{4-[(3,5-dichloroisonicotnoyl)amino]phenyl}-2-(2,4,4-trimethyl-3-oxo-cyclobut-1-enylamino)propanoate

Prepared in a similar manner to the compound of Example 151 fromIntermediate 59 to give the title compound (70%). δH (CDCl₃) 8.78 (1H,br s), 8.44 (2H, s), 7.52 (2H, d, J 8.4 Hz), 7.04 (2H, d, J 8.3 Hz),5.55 (1H, d J 9.0 Hz), 4.39 (1H, m), 4.20 (2H, q, J 7.1 Hz), 3.07 (2H,m), 1.41 (3H, s), 1.26 (3H, t, J 7.1 Hz), 1.05 (6H, s); m/z (ES⁺, 70V)490.0 (MH⁺).

EXAMPLE 154(2S)-3-{4-[(3.5-Dichloroisonicotinoyl)amino]phenyl}-2-(2,4,4-trimethyl-3-oxo-cyclobut-1-enylamino)propanoicacid

The compound of Example 153 was hydrolysed by the method of Example 2 toafford the title compound (69%). δH (DMSO d⁸) 7.86 (2H, s), 6.82 (2H, d,J 8.5 Hz), 6.54 (2H, d, J 8.5 Hz), 3.69 (1H, m), 2.57 (1H, m), 2.25 (1H,m), 0.68 (3H, s), 0.38 (3H, s), 0.29 (s, 3H); m/z (ES⁺, 70V) 462.0(MH⁺).

EXAMPLE 155 Ethyl(2S)-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}-2-(2-ethyl-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)propanoate

Prepared in a similar manner to the compound of Example 151 fromIntermediate 60 to give the title compound (73%). δH (DMSO d⁶) 8.78 (2H,s), 8.13 (1H, d, J 9.0 Hz), 7.59 (2H, d, J 8.4 Hz), 7.30 (2H, d, J 8.3Hz), 4.25 (1H, m), 4.17 (2H, q, J 7.0 Hz), 3.12 (1H, m), 3.00 (1H, m),1.83 (2H, m), 1.20 (4H, m), 1.06 (3H, m), 0.98 (3H, s), 0.84 (3H, t, J7.5 Hz); m/z (ES⁺, 70V) 504.0 (MH⁺).

EXAMPLE 156(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-ethyl-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)propanoic acid

The compound of Example 155 was hydrolysed by the method of Example 2 toafford the title compound (78%). δH (DMSO d⁶) 7.83 (2H, s), 6.81 (2H, d,J 8.5 Hz), 6.51 (2H, d, J 8.4 Hz), 3.52 (1H, m), 2.51 (1H, m), 2.21 (1H,m), 1.10 (2H, q, J 7.3 Hz), 0.36 (3H, s), 0.26 (3H, s), 0.10 (3H, t, J7.5 Hz); m/z (ES⁺, 70V) 476.0 (MH⁺).

EXAMPLE 157 Ethyl(2S)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}-2-(4,4-dimethyl-3-oxo-2-propyl-cyclobut-1-enylamino)propanoate

Prepared in a similar manner to the compound of Example 151 fromIntermediate 61 to give the title compound (75%). δH (DMSO d⁶) 8.80 (2H,s), 8.11 (1H, d, J 9.3 Hz), 7.59 (2H, d, J 8.3 Hz), 7.30 (2H, d, J 8.3Hz), 4.26 (1H, m), 4.15(2H, q, J 7.1 Hz), 3.12 (1H, m), 3.00 (1H, m),1.75 (2H, m), 1.23 (2H,m), 1.07 (3H, s), 0.99 (3H, s), 0.73 (3H, t, J7.3 Hz); m/z (ES⁺, 70V) 518.0 (MH⁺).

EXAMPLE 158(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(4.4-dimethyl-3-oxo-2-propyl-cyclobut-1-enylamino)propanoicacid

The compound of Example 157 was hydrolysed by the method of Example 2 toafford the title compound (93%). δH (DMSO d⁶) 8.78 (2H, s), 8.05 (1H, d,J 9.2 Hz), 7.58 (2H, d, J 8.3 Hz), 7.30 (2H, d, J 8.3 Hz), 4.15 (1H, m),3.13 (1H, m), 2.95 (1H, m), 1.75 (2H, m), 1.23 (2H, q, J 7.3 Hz), 1.06(3H, s), 0.98 (3H, s), 0.72 (3H, t, J 7.3 Hz); m/z (ES⁺, 70V) 490.0(MH⁺).

EXAMPLE 159 Ethyl(2S)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}-2-(2-methyl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoate

Prepared in a similar manner to the compound of Example 151 fromIntermediate 64 to give the title compound (68%). δH (DMSO d⁶) 8.79 (2H,s), 7.93 (2H, d, J 8.9 Hz), 7.58 (2H, d, J 8.4 Hz), 7.29 (2H, d, J 8.4Hz), 4.33 (1H, m), 4.16 (2H, q, J 7.1 Hz), 3.10 (1H, m), 2.99 (1H, m),1.60 (10H, m), 1.37 (3H, s), 1.18 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V)530.1 (MH⁺).

EXAMPLE 160(2S)-3-{4-[(3.5-Dichloroisonocotinoyl)amino]phenyl}-2-(2-methyl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoicacid

The compound of Example 159 was hydrolysed by the method of Example 2 toafford the title compound (86%). δH (DMSO d⁶) 8.82 (2H, s), 7.81 (1H, d,J 9.1 Hz), 7.57 (2H, d, J 8.4 Hz), 7.30 (2H, d, J 8.4 Hz), 4.28 (1H, m),3.13 (1H, m), 2.96 (1H, m), 1.70-1.49 (8H, m), 1.38 (3H, s), 1.14 (2H,m); m/z (ES⁺, 70V) 501.9 (MH⁺).

EXAMPLE 161 Ethyl(2S)-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-propyl-spiro[3.5]non-1-en-1-ylamino)propanoate

Prepared in a similar manner to the compound of Example 151 fromIntermediate 65 to give the title compound (76%). δH (CDCl₃) 8.58 (2H,s), 8.44 (1H, s), 7.65 (2H, d, J 8.5 Hz), 7.16 (2H, d, J 8.4 Hz), 5.38(1H, m), 4.46 (1H, m), 4.30 (2H, q, J 7.1 Hz), 3.17 (2H, m), 1.851.42(14H, m), 1.38 (3H, t, J 7.1 Hz), 0.90 (3H, t, J 7.3 Hz); m/z (ES⁺, 70V)558.1 (MH⁺).

EXAMPLE 162(2S)-3-{4-[(3,5-Dichlorolsonicotinoyl)amino]Phenyl}-2-(3-oxo-2-propyl-spiro[3.5]non-1-en-1-ylamino)propanoicacid

The compound of Example 161 was hydrolysed by the method of Example 2 toafford the title compound (84%). δH (DMSO d⁶, 380K) 10.42 (1H, br s),8.69 (2H, s), 7.57 (2H, d, J 7.3 Hz), 7.28 (d, 2H, J 8.3 Hz), 7.12 (1H,d, J 9.1 Hz), 4.21 (1H, m), 3.20 (1H, dd, J 14.0, 4.9 Hz), 3.06 (1H, dd,J 14.0, 8.8 Hz), 1.87 (2H, m), 1.72-1.45 (10H, m), 1.36 (2H, m), 1.23(1H, m), 0.82 (3H, t, J 7.4 Hz); m/z (ES⁺, 70V) 530.1 (MH⁺).

EXAMPLE 163 Ethyl(2S)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}-2-(2-methyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1-ylamino)propanoate

Prepared in a similar manner to the compound of Example 151 fromIntermediate 68 to give the title compound (71%). δH NMR (DMSO d⁶) 8.80(2H, s), 8.11 (1H, d, J 9.1 Hz), 7.59 (2H, d, J 8.4 Hz), 7.30 (2H, d, J8.4 Hz), 4.38 (1H, m), 4.17 (2H, q, J 7.1 Hz), 3.75 (2H, m), 3.60 (2H,m), 3.15 (1H, dd, J 13.7, 5.1 Hz), 2.99 (1H, dd, J 13.6, 9.2 Hz), 1.90(2H, m), 1.39 (3H, s), 1.19 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 532.0(MH⁺).

EXAMPLE 164(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-methyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1-ylamino)propanoicacid

The compound of Example 163 was hydrolysed by the method of Example 2 toafford the title compound (89%). δH (DMSO d⁶) 8.81 (2H, s), 8.05 (1H, d,J 9.2 Hz), 7.60 (2H, d, J 8.4 Hz), 7.32 (2H, d, J 8.4 Hz), 4.25 (1H, m),3.75 (2H, m), 3.58 (2H, m), 3.13 (1H, dd, J 13.8, 4.6 Hz), 2.98 (1H, dd,J 13.8, 9.5 Hz), 1.94 (2H, m), 1.40 (3H, s), 1.29 (2H, m); m/z (ES⁺,70V) 504.0 (MH⁺).

EXAMPLE 165 Ethyl(2S)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-propyl-7-oxa-spiro[3.5]non-1-en-1-ylamino)propanoate

Prepared in a similar manner to the compound of Example 151 fromIntermediate 69 to give the title compound (59%). δH (DMSO d⁶) 8.78 (2H,s), 8.08 (1H, d, J 8.8 Hz), 7.55 (2H, d, J 8.4 Hz), 7.29 (2H, d, J 8.5Hz), 4.23 (1H, m), 4.16 (2H, q, J 7.1 Hz), 3.76 (2H, m), 3.58 (2H, m),3.15 (1H, dd J 13.6, 4.8 Hz), 2.98 (1H, dd, J 13.6, 9.7 Hz), 1.80 (2H,m), 1.18 (6H, m), 0.73 (3H, t, J 7.4 Hz); m/z (ES⁺, 70V) 560.0 (MH⁺).

EXAMPLE 166 Ethyl(2S)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-propyl-7-oxa-spiro[3.5]non-1-en-1-ylamino)propanoate

The compound of Example 165 was hydrolysed by the method of Example 2 toafford the title compound (82%). δH (DMSO d⁶, 380K) 10.39 (1H, br s),8.68 (2H, s), 7.57 (2H, m), 7.33 (3H, m), 4.23 (1H, m), 3.70 (4H, m),3.21 (1H, dd, J 14.0, 4.8 Hz), 3.04 (1H, dd, J 14.0, 9.0 Hz), 2.10 (1H,s), 1.88 (4H, m), 1.87 (3H, t, J 7.0 Hz), 1.40 (4H, m); m/z (ES⁺, 70V)532.1 (MH⁺).

EXAMPLE 167 2-Imidazol-1-yl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared in a similar manner to the compound of Example 138 fromN-2-hydroxyethylimidazole [prepared according to the method of Yoshinoet al, J. C. S. Perkin Trans. 1, 1977, 1266-72] to give the titlecompound (48%). δH (DMSO d⁶) 10.88 (1H, s), 8.88 (1H, d, J 9.1 Hz), 8.79(2H, s), 7.66 (1H, s), 7.58 (2H, d, J 8.5 Hz), 7.29 (2H, d, J 8.5 Hz),6.89 (1H, s), 4.84 (1H, m), 4.39 (2H, m), 4.29 (2H, m), 3.16 (1H, dd, J13.9, 4.6 Hz), 2.96 (1H, dd, J 13.9, 9.7 Hz), 1.75-1.45 (8H, m), 1.35(1H, m), 1.13 (1H, m); m/z (ES⁺, 70V) 662.1 (MH⁺).

EXAMPLE 1682-(2-Bromo-3-oxo-7-oxa-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3-methyl-[2.7]naphthyridine-1-yl)amino]phenyl}propanoicacid

Prepared by the methods as described herein (77%). δH (d⁶ DMSO) 8.77(1H, s), 7.67 (1H, d, J 6.3 Hz), 6.96 (2H, d, J 8.5 Hz), 6.78 (1H, d, J5.8 Hz), 6.45 (2H, d, J 8.5 Hz), 6.14 (1H, s), 4.19 (1H, m), 3.05-2.85(4H, m), 2.59 (1H, dd, J 14.0, 4.4 Hz), 2.25 (1H, dd, J 13.9, 9.7 Hz),1.66 (3H, s), 1.28 (1H, m), 1.16 (1H, m), 0.83 (1H, d, J 13.5 Hz), 0.66(1H, d, J 13.5 Hz); m/z (ES⁺, 70V) 537.9 (MH⁺).

EXAMPLE 169 Ethyl(2S)-3-{4[(3,5-dichloroisonicotinoyl)amino]phenyl}-2-(2-[1,3]dithian-2-yl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoate

To a solution of the compound of Example 27 (1.5 g, 2.9 mmol) in DCM(100 ml) was added 1,3-dithienium tetrafluorborate (3.0 g, 14 mmol)[prepared by the method of Paterson I; Price L. G. Tet. Lett. 1981, 22(29), 2829]. The mixture was stirred overnight and then partitionedbetween EtOAc (200 ml) and sodium carbonate (100 ml, sat. aq.), theorganics were separated, washed with water (3×50 ml), brine (50 ml),dried (Na₂SO₄), filtered and concentrated in vacuo to give a crudeproduct which was purified by column chromatography (SiO₂, EtOAc:hexane4:1) to give the title compound as a pale yellow solid (0.6 g, 86%) δH(400 MHz, DMSO d⁶, 300K) 8.67 (2H, s), 8.15 (1H, d, J 9.5 Hz), 7.67 (2H,d, J 8.5 Hz), 7.12 (2H, d, J 8.5 Hz), 5.06 (1H, m), 4.65 (1H, s),1.10(1H, m), 4.08 (2H, t, J 7.1 Hz), 3.17-2.72 (3H, m), 2.65 (2H, m), 1.95(1H, m), 1.87 (1H, m), 1.78-1.46 (11H, m), 1.25 (1H, d, J 12.3 Hz); m/z(ES⁺, 70V) 634 (MH⁺).

EXAMPLE 170(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-[1,3]dithian-2-yl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoic acid

To a solution of the compound of Example 169 (0.25 g, 0.4 mmol) in THF(2 ml) was added a solution of lithium hydroxide (25 mg, 0.6 mmol) inwater (1 ml). The mixture was stirred at room temperature overnight,concentrated in vacuo and the residue dissolved in the minimum amount ofwater. HCl (2M, aq.) was added until the pH of the solution was 4, theresulting solid was filtered, washed with ether and ethyl acetate togive the product as a pale yellow solid (0.15 g, 63%). δH (400 MHz, DMSOd⁶, 300K) 10.85 (1H, s), 8.78 (2H, s), 8.28 (1H, d, J 9.9 Hz), 7.55 (2H,d J 8.5 Hz), 7.31 (2H, d, J 8.5 Hz), 5.06 (1H, m), 4.75 (1H, s),3.21-2.78 (3H, m), 2.67 (2H, m), 1.99 (1H, m), 1.75 (1H, m), 1.57 (8H,m), 1.22 (1H, d, J 11.9 Hz), 1.08 (1H, m); m/z (ES⁺, 70V) 606 (MH⁺).

EXAMPLE 171 Ethyl(2S)-3-{4-[(3.5-dichloro-1-oxy-pyridine-4-carbonyl)amino]-phenyl}-2-(2-methanesulfinyl-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)propanoate

A solution of the compound of Example 5 (800 mg, 1.68 mmol) in THF (20ml) was treated at rt with a solution of methanesulfenyl chloride in DCM(1.9 ml, 1.0M). After 30 min the reacton was partitioned between EtOAc(50 ml) and saturated aqueous sodium hydrogencarbonate (25 ml).Separation of the organic phase, drying (MgSO₄), filtration andconcentration in vacuo gave a solid which was approx. 90% pure. Thecrude solid was redissolved in DCM (20 ml) and treated with mCPBA (1.5g, 57-75% purity) and sodium hydrogencarbonate (500 mg) and stirred atrt for 24 h. The reaction was diluted with EtOAc (100 ml), washed withH₂O (50 ml), separated, dried (MgSO₄), filtered and concentrated invacuo. Chromatography (SiO₂, EtOAc) gave the title compound as a whitepowder (730 mg, 1.31 mmol, 78%) as an approx. 1:1 mixture ofdiastereomers. δH (CDCl₃, 330K) 8.44 and 8.41 (2H, s), 8.35 and 8.17(1H, s), 7.57 and 7.47 (2H, d, J 8.4 Hz), 7.15 and 7.08 (2H, d, J 8.4Hz), 7.04 and 7.01 (1H, d, J 8.9 Hz), 5.24-5.22 (1H, m), 4.25-4.11 (3H,m), 3.31-3.05 (2H, m), 2.97 and 2.93 (3H, s), 1.30-1.16 (9H, m); m/z(ES⁺, 70V) 553.9 and 556.0 (MH⁺).

EXAMPLE 172(2S)-3-{4-[(3.5-Dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}-2-(2-methanesulfinyl-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)propanoicacid

The compound of Example 171 (300 mg, 0.54 mmol) was hydrolysed in asimilar manner to the method of Example 2, to give the title compound asa white powder (239 mg, 0.45 mmol, 83%) as an approx. 1:1 diasteromericmixture. δH (DMSO d⁶, 390K) 9.75 (1H, br s), 8.77 (2H, s), 7.56 (2H, d,J 8.5 Hz), 7.25 (2H, d, J 8.5 Hz), 4.99 (1H, m), 3.18-2.98 (2H, m), 2.85(3H, s), 1.18 (3H, s), 1.06 (3H, s); m/z (ES⁺, 70V) 525.9 and 527.9(MH⁺).

EXAMPLE 173(2S)-2-[2-(Methylsulfanyl)-3-oxospiro[3.5]non-1-en-1-yl]amino-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoicacid

The ethyl ester of the title compound was prepared in two steps from thefree amine of Intermediate 12 (1.40 g, 0.41 mmol),spiro[3.5]nonane-1,3-dione (650 mg, 0.42 mmol) [prepared according tothe method of Wasserman, H. H. et al, J. Org. Chem., 38, 1451-1455(1973)] and a 1.0M solution of methyl sulfenyl chloride in DCM (0.5 ml,0.5 mmol) according to the method of Example 108 (1.53 g, 0.30 mmol,71%). This ester was then subjected to hydrolysis according to themethod of Example 2 to give the title compound as a yellow powder (1.15g, 0.23 mmol, 57%). δH (DMSO d⁶, 390K) 9.80 (1H, s), 8.61 (1H, d, J 5.6Hz), 8.13 (1H, d, J 5.4 Hz), 7.67 (2H, d, J 8.3 Hz), 7.60 (1H, d, J 5.5Hz), 7.18 (1H, d, J 8.3 Hz), 7.05 (1H, d, J 5.5 Hz), 4.37 (1H, m),3.22-3.12 (2H, m), 2.14 (3H, s), 1.85-1.10 (10H, m); m/z (ES⁺, 70V)489.1 (MH⁺).

EXAMPLE 174 Ethyl(2S)-2-[2-(methylsulfanyl)-3-oxo-7-oxaspiro[3.5]non-1-en-1-yl]amino-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoate

Was prepared in two steps from the free amine of Intermediate 12 (1.40g, 0.41 mmol), 7-oxaspiro[3.5]nonane-1,3-dione (650 mg, 0.42 mmol)[prepared according to the method of Wasserman, H. H. et al, J. Org.Chem., 38, 1451-1455 (1973)] and a 1.0M solution of methyl sulfenylchloride in DCM (0.5 ml, 0.5 mmol) according to the method of Example108 to give the title compound as a yellow powder (1.21 g, 0.23 mmol,55%). δH (DMSO d⁶, 390K) 9.82 (1H, s), 9.55 (1H, s), 8.93 (1H, d, J 9.2Hz), 8.65 (1H, d, J 5.6 Hz), 8.15 (1H, d, J 5.7 Hz), 7.78 (2H, d, J 8.5Hz), 7.68 (1H, d, J 5.6 Hz), 7.23 (2H, d, J 8.5 Hz), 7.13 (1H, d, J 5.7Hz), 5.16-5.10 (1H, m), 4.20 (2H, q, J 7.1 Hz), 3.77 (2H, m), 3.59-3.52(2H, m), 3.21 (1H, dd, J 13.8, 4.5 Hz), 2.98 (1H, dd, J 13.8, 10.2 Hz),1.96 (3H, s), 1.48-1.32 (4H, m), 1.23 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V)519.1 (MH⁺).

EXAMPLE 175(2S)-2-[2-(Methylsulfanyl)-3-oxo-7-oxaspiro[3.5]non-1-en-1-yl]amino-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoicacid

Hydrolysis of the compound of Example 174 (650 mg, 0.12 mmol) withlithium hydroxide (30 mg, 0.7 mmol), according to the method of Example2, gave the title compound as a pale yellow powder (501 mg, 0.10 mmol,85%). δH (DMSO d⁶, 390K) 9.83 (1H, s), 9.54 (1H, s), 8.70 (1H, d, J 8.9Hz), 8.65 (1H, d, J 5.6 Hz), 8.14 (1H, d, J 5.7 Hz), 7.75 (2H, d, J 8.5Hz), 7.68 (1H, d, J 5.6 Hz), 7.21 (2H, d, J 8.5 Hz), 7.11 (1H, d, J 5.7Hz), 4.92 (1H, m), 3.76-3.73 (2H, m), 3.62-3.54 (2H, m), 3.23 (1H, d, J13.6, 3.9 Hz), 2.94 (1H, dd, J 13.6, 9.9 Hz), 1.91 (3H, s), 1.47-1.28(4H, m); m/z (ES⁺, 70V) 491.1 (MH⁺).

EXAMPLE 176 Methyl(2S)-2-[(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-[4-([2,7]naphthyridin-1-yloxy)phenyl]propanoate

A stirred solution containing Intermediate 13 (300 mg, 0.72 mmol) in THF(10 ml) at rt was treated dropwise with a 1.0M solution of bromine inTHF (1.0 ml, 1 mmol). After 2 h the reaction was diluted with EtOAc (50ml), washed with saturated aqueous sodium hydrogencarbonate solution(2×25 ml), dried (MgSO₄) and concentrated in vacuo. Chromatography(SiO₂, EtOAc) gave the title compound as a white powder (217 mg, 0.43mmol, 61%). δH (DMSO d⁶, 360K) 9.71 (1H, s), 8.71 (1H, d, J 5.7 Hz),8.04 (1H, d, J 5.8 Hz), 7.56 (1H, d, J 5.7 Hz), 7.23-7.13 (5H, m), 6.19(1H, d, J 8.1 Hz), 5.06-5.02 (1H, m), 3.79 (3H, s), 3.26 (2H, m), 1.19(6H, s); m/z (ES⁺, 70V) 497.9 (MH⁺).

EXAMPLE 177(2S)-2-[(2-Bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-[4-([2,7]naphthyridin-1-yloxy)phenyl]propanoicacid

Hydrolysis of the compound of Example 176 (80 mg, 0.016 mmol) with LiOH(10 mg, 0.023 mmol) according to the method of Example 2 gave the titlecompound as a white powder (51 mg, 0.01 mmol, 63%). δH (DMSO d⁶, 360K)9.71 (1H, s), 8.81 (1H, d, J 5.5 Hz), 8.14 (1H, d, J 5.4 Hz), 7.87 (1H,d, J 5.2 Hz), 7.52 (1H, d, J 5.4 Hz), 7.38 (2H, d, J 8.5 Hz), 7.28 (2H,d J 8.5 Hz), 4.87-4.84 (1H, m), 3.31-3.15 (2H, m), 1.18 (3H, s), 1.10(3H, s); m/z (ES⁺, 70V) 483.9 (MH⁺).

EXAMPLE 178N⁴-(4-[3-(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)-5-oxo-1.3-oxazolan-4-yl]methylphenyl)-3,5-dichloroisonicotinamide

A solution containing the compound of Example 32 (1.0 g, 1.76 mmol),finely ground potassium carbonate (500 mg) and DMAP (50 mg, 0.4 mmol),in DMF (14 ml) was treated dropwise with chloromethyl pivalate (0.5 ml)at room temperature. After 24 h the reaction was diluted with EtOAc (150ml), washed with brine (3×50 ml), dried (MgSO₄) and concentrated invacuo. Chromatography (SiO₂, 1:1 EtOAc:hexanes) gave the title compoundas a white powder (475 mg, 0.82 mmol, 47%). δH (DMSO d⁶, 390K) 10.97(1H, s), 8.80 (2H, s), 7.63 (2H, d, J 8.5 Hz), 7.17 (2H, d, J 8.5 Hz),5.41 (1H, d, J 3.9 Hz), 4.95 (1H, m), 4.69 (1H, d, J 3.9 Hz), 3.39-3.29(2H, m), 1.99-1.06 (10H, m); m/z (ES⁺, 70V) 580.9 (MH⁺).

EXAMPLE 1793-[2-(Isopropylsulfanyl)-3-oxospiro[3.5]non-1-en-1-yl]-4-[4-([2,7]naphthyridin-1-ylamino)benzyl]-1,3-oxazolan-5-one

Prepared from the compound of Example 121 (450 mg, 0.88 mmol) in asimilar manner to the compound of Example 178 to give the title compoundas an off-white powder (390 mg, 0.73 mmol, 84%). δH (DMSO d⁶, 390K) 9.57(1H, s), 8.64 (1H, d, J 5.7 Hz), 8.24 (1H, d, J 5.8 Hz), 8.17 (1H, s),7.74 (2H, d, J 8.4 Hz), 7.53 (1H, d, J 5.6 Hz), 7.16 (2H, d, J 8.4 Hz),7.06 (1H, d, J 5.8 Hz), 5.20 (1H, br s), 4.93 (1H, br s), 4.26 (1H, brs), 3.58 (1H, br s), 3.33 (1H, br s), 3.27 (1H, m), 1.99-1.06 16H, m);m/z (ES⁺, 70V) 529.2 (MH⁺).

EXAMPLE 180 Neopentyl(2S)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Using a similar procedure to that for the preparation the compound ofExample 138 from the compound of Example 32 (0.5 g, 0.89 mmol), EDC (191mg, 1.0 mmol), HOBT (120 mg, 0.89 mmol), neopentyl alcohol (0.4 g, 4.5mmol) and DMF (15 ml) was prepared, after purification by chromatography(SiO₂, EtOAc), the title compound as a white powder (400 mg, 0.63 mmol,71%). δH (DMSO d⁶, 390K) 10.87 (1H, s), 8.92 (1H, d, J 9.1 Hz), 8.79(2H, s), 7.58 (2H, d, J 8.5 Hz), 7.32 (2H, d, J 8.5 Hz), 4.88-4.82 (1H,m), 3.86 (1H, d, J 10.4 Hz), 3.80 (1H, d, J 10.4 Hz), 3.26 (1H, dd, J13.9, 4.8 Hz), 3.03 (1H, dd, J 13.9, 10.1 Hz), 1.99-1.06 (10H, m), 0.91(9H, br s); m/z (ES⁺, 70V) 638.0 (MH⁺).

EXAMPLE 181 Isopropyl(2S)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}-2-(2-methyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1-ylamino)propanoate

Prepared in a similar manner to the compound of Example 138 from thecompound of Example 164 to give the title compound in 79% yield. δH(DMSO d⁶) 10.87 (1H, s), 8.80 (2H, s), 8.10 (1H, d, J 8.9 Hz), 7.59 (d,2H, J 8.2 Hz), 7.31 (d, 2H, J 8.2 Hz), 4.98 (1H, m), 4.30 (1H, m), 3.76(2H, m), 3.60 (2H, m), 3.11 (1H, dd, J 13.7, 5.3 Hz), 3.00 (1H, dd, J13.2, 9.1 Hz), 2.00-1.80 (2H, m), 1.42 (3H, s), 1.17 (6H, m); m/z (ES⁺,70V) 546.1 (MH⁺).

EXAMPLE 182 5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}propanoate

To a stirred solution of the compound of Example 32 (1.0 g, 1.76 mmol)and potassium carbonate (484 mg, 3.52 mmol) in DMF (20 ml) at 0° C. wasadded Intermediate 73 (408 mg, 2.12 mmol) in one portion. The ice-bathwas removed and the mixture allowed to stir at room temperature for 3hours. The mixture was poured into ice/water and extracted with EtOAc.The extract was washed three times with brine, dried (MgSO₄) and thesolvent removed in vacuo to afford a yellow solid. Chromatography (SiO₂,1:1 hexane:EtOAc) gave the title compound as a white solid (686 mg,57%). δH (DMSO d⁶) 10.90 (1H, s), 8.95 (1H, d, J 8.9 Hz), 8.80 (2H, s),7.60 (2H, d, J 8.3 Hz), 7.26 (2H, d, J 8.3 Hz), 4.86 (1H, m), 3.22 (1H,m, J 4.0, 13.6 Hz), 3.06 (1H, m, J 13.2, 10.7 Hz), 2.17 (3H, s),1.74-1.38 (10H, m); m/z (ES⁺, 70V) 680.0 (MH⁺).

EXAMPLE 183 2,3-Dihydroxy-propyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared in a similar manner to the compound of Example 138 from thecompound of Example 32 and glycerol to give the title compound in 48%yield after chromatography on silica gel. δH (DMSO d⁶) 10.91 (1H, s),8.91 (1H. d, J 9.2 Hz), 8.80 (2H, s), 7.60 (2H, d, J 8.5 Hz), 7.28 (2H,d, J 8.3 Hz), 5.01 (1H, m), 4.85 (1H, m), 4.71 (1H, m), 4.20 (1H, m),4.09 (1H, m), 3.71 (1H, m), 3.57 (1H, m), 3.26 (1H, dd, J 13.8, 3.9 Hz),3.04 (1H, dd, J 13.8, 9.3 Hz), 1.80-1.45 (10H, m); m/z (ES⁺, 70V) 640.0(MH⁺).

EXAMPLE 184 Tetrahydro-furan-3-ylmethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared in a similar manner to the compound of Example 138 from thecompound of Example 32 and tetrahydrofurfuryl alcohol to give the titlecompound (52%) after chromatography on silica gel. δH (DMSO d⁶) 10.88(1H, s), 8.93 (1H, d, J 9.1 Hz), 8.80 (2H, s), 7.60 (2H, d, J 8.3 Hz),7.28 (2H, d, J 6.9 Hz), 4.84 (1H, m), 4.15 (2H, m), 4.05 (1H, m), 3.23(1H, dd, J 13.8, 4.4 Hz), 3.04 (1H, dd, J 13.6, 9.6, Hz), 2.00-1.50(14H, m); m/z (ES⁺, 70V) 650.1 (MH⁺).

EXAMPLE 185 Tetrahydropyran-4-yl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared in a similar manner to the compound of Example 138 from thecompound of Example 32 (0.5 g, 0.89 mmol), EDC (300 mg), HOBT (200 mg)and 4-hydroxytetrahydropyran (0.8 ml) in DMF (5 ml) to give the titlecompound (0.42 g, 74%). δH (300 MHz, DMSO d⁶) 11.02 (1H, br), 9.04 (1H,d, J 9.0 Hz), 8.92 (2H, s), 7.73 (2H, d, J 8.4 Hz), 7.42 (2H, d, J 8.5Hz), 5.13 (1H, br), 4.93 (1H, br), 3.87 (2H, br), 3.60 (2H, br), 3.36(1H, dd, J 14.0, 5.1 Hz), 3.18 (1H, dd, J 13.9, 9.3 Hz), 1.61-2.06 (12H,m), 1.52 (2H, d, J 12.6 Hz), 1.26 (2H, br); m/z (ES⁺, 70V) 652 (MH⁺).

EXAMPLE 186 Isopropyl(2S)-2-(2-bromo-3-oxo-7-oxa-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

To a solution of the isopropyl ester of the compound of Example 40 (0.4g, 8.1 mmol) [prepared in a similar manner to the compound of Example138] in THF (5 ml) at room temperature was added NBS (0.3 g). Themixture was stirred for 2 h and then partitioned between water (100 ml)and EtOAc (100 ml), the organics were separated and washed with water(3×50 ml), brine (50 ml), dried (Na₂SO₄), filtered and concentrated invacuo to give a crude oil. Purification by column chromatography(hexane:EtOAc, 3:2) gave the title compound as a white solid (0.24 g,52%). δH (400 MHz, DMSO d⁶) 9.02 (1H, d, J 9.0 Hz), 8.79 (2H, s), 7.59(2H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 4.97 (1H, m), 4.75 (1H, m),3.80 (2H, m), 3.58 (2H, q, J 11.7 Hz), 3.20 (1H, dd, J 13.0, 5.0 Hz),3.03 (1H, dd, J 13.0, 9.4, Hz), 1.97 (2H, m), 1.49 (1H, dd, J 13.0, 1.6Hz), 1.33 (1H, dd, J 13.2, 1.6 Hz), 1.23 (3H, d, J 11.3 Hz), 1.19 (3H,d, J 11.4 Hz); m/z (ES⁺, 70V) 612 (MH⁺).

EXAMPLE 187 Ethyl(2S)-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}-2-(4,4-dimethyl-2-methylsulfanyl-3-oxo-cyclobut-1-enylamino)propanoate

A mixture of Intermediate 43 (0.44 g, 1.15 mmol) and3-hydroxy-4,4-dimethyl-2-cyclobutenone (0.14 g, 1.1eq) was stirred atroom temperature for a period of 17 h. The mixture was concentrated invacuo and triturated with diethyl ether and the resulting solidre-dissolved in THF (10 ml). The solution was treated with a solution ofmethanesulfenyl chloride at 0-5° C. in DCM until TLC analysis of themixture indicated complete consumption of starting material. The mixturewas partitioned between EtOAc (50 ml) and water (50 ml), the organicswere separated and and washed with water (2×50 ml), brine (50 ml), dried(MgSO4), filtered and concentrated to give a crude white foam.Purification by column chromatography (EtOAc:hexane, 1:1) gave the titlecompound as a white solid (0.55 g, 91%). δH (400 MHz, DMSO d⁶) 11.16(1H, br), 8.87 (1H, d, J 9.0 Hz), 8.82 (s, 2H), 8.72 (1H, d, J 2.5 Hz),8.05 (1H, dd, J 8.4, 2.5 Hz), 7.35 (1H, d, J 8.4 Hz), 5.33 (1H, m), 4.18(2H, q, J 7.1 Hz), 3.36 (1H, dd, J 14.1, 5.0 Hz), 3.32 (3H, s), 3.20(1H, dd, J 14.1, 9.4 Hz), 0.94 (3H, s), 1.09 (3H, s), 1.21 (3H, t, J 7.1Hz); m/z (ES⁺, 70V) 523 (MH⁺).

EXAMPLE 188 Isopropyl(2S)-3-{5-[(3.5-dichloroisonicotinoyl)amino]pyridin-2-yl}-2-(4,4-dimethyl-2-methylsulfanyl-3-oxo-cyclobut-1-enylamino)propanoate

Hydrolysis of the compound of Example 187 (0.35 g, 0.67 mmol) accordingto the method of Example 2 and re-esterified with isopropanol (EDC,HOBT, DMF) gave the title compound as a white solid (65 mg, 18%). δH(400 MHz, DMSO d⁶) 11.16 (1H, br), 8.85 (1H, d, J 8.9 Hz), 8.82 (2H, s),8.72 (1H, d, J 1.8 Hz), 8.04 (1H, m), 7.35 (1H, d, J 8.3 Hz), 5.28 (1H,m), 5.00 (1H, m), 3.35 (1H, dd, J 14.1, 5.0 Hz), 3.32 (3H, s), 3.18 (1H,dd, J 14.1, 9.3 Hz), 1.22 (6H, m), 1.09 (3H, d, J 1.2 Hz), 0.95 (3H, d,J 1.2 Hz); m/z (ES⁺, 70V) MH⁺ 537.

EXAMPLE 190 Ethyl(2S)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}-2-(3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoate

Intermediate 75 (170 mg, 0.42 mmol) and 1-keto-3-hydroxy[3,5]-non-2-ene(200 mg, 1.3 mmol) were stirred together at room temperature overnightin THF (5 ml) The reaction mixture was diluted with DCM (50 ml), washedwith sodium bicarbonate solution. (saturated, 2×50 ml), dried (MgSO₄)and reduced in vacuo to give a yellow solid. The residue waschromatographed (SiO₂ DCM:methanol, 98:2) to give the title compound asa white powder (120 mg). δH (CDCl₃) 9.03 (1H, br s), 8.11 (2H, s), 7.64(2H, d, J 7.9 Hz) 7.18 (2H, d, J 7.5 Hz), 5.01 (1H, m), 4.22 (1H, m),4.21 (2H, q, J 7.1 Hz), 3.12 (2H, m), 1.45 (10H, m), 1.30 (3H, t, J 7.1Hz); m/z (ES⁺, 70V) 532.0 (MH⁺).

EXAMPLE 191(2S)-3-{4-[(3,5-Dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}-2-(3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoicacid

The compound of Example 190 (30 mg, 0.056 mmol) was hydrolysed by themethod of Example 2 to afford the title compound as white powder (20mg). δH (CD₃OD) 8.46 (2H, s), 7.47 (2H, d, J 8.5 Hz), 7.18 (2H, d, J 8.5Hz), 4.14 (1H, m), 3.21 (1H, m), (obscured by MeOH/water) 2.83 (1H, dd,J 9.6, 4.2 Hz), 1.80-1.10 (9H, m), 1.07 (3H, t, J 7.1 Hz); m/z (ES⁺,70V) 505.0 (MH⁺).

EXAMPLE 192 Ethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3.5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoate

Prepared from the compound of Example 190 (85 mg, 0.16 mmol) in asimilar manner to the compound of Example 31 to give the title compound(80 mg). δH (CDCl₃) 8.94 (1H, br s), 8.14 (2H, s), 7.62 (2H, d, J 8.4Hz), 7.13 (2H, d, J 8.3 Hz), 5.88 (1H, m), 5.00 (1H, m), 4.26 (2H, q, J7.1 Hz), 3.26 (2H, m), 2.03-1.41 (10H, m), 1.35 (3H, t, J 7.1 Hz); m/z(ES⁺, 70V) 612.0 (MH⁺).

EXAMPLE 193(2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoicacid

The compound of Example 192 was hydrolysed by the method of Example 2 toafford the title compound. δH (DMSO d⁶) 10.80 (1H, s) 8.73 (2H, s), 7.55(2H, d, J 8.0 Hz), 7.24 (2H, d, J 8.4 Hz), 4.65 (1H, m), 3.22 (1H, dd, J13.8, 4.4 Hz,), 3.00 (1H, dd, J 13.7, 4.4 Hz), 1.82-1.00 (11H, m).

EXAMPLE 194 Ethyl(2S)-2-(2-chloro-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoate

Prepared in a similar manner to the compound of Example 61 from thecompound of Example 190 (500 mg, 0.94 mmol) and N-chlorosuccinimide (150mg, 1.13 mmol) to give the title compound as a white powder (220 mg). δH(DMSO d⁶) 10.85 (1H, s), 8.84 (1H, d, J 9.0 Hz), 8.75 (2H, s), 7.58 (2H,d, J 8.5 Hz) 7.27 (2H, d, J 8.5 Hz), 4.68 (1H, m) 4.20 (2H, q, J 7.0 Hz)3.22 (1H, dd, J 13.8, 4.7 Hz) 3.01 (1H, dd, J 13.7, 9.7 Hz) 1.74-1.55(9H, m) 1.38 (1H, m) 1.23 (3H, m, J 7.1 Hz) 1.13 (1H, m); m/z (ES⁺, 70V)568.0 (MH⁺).

EXAMPLE 195(2S)-2-(2-Chloro-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoicacid

The compound of Example 194 was hydrolysed by the method of Example 2 toafford the title compound. δH (DMSO d⁶) 10.83 (1H, s), 8.75 (m, 3H),7.57 (2H, d, J 8.4 Hz) 7.26 (2H, d, J 8.5 Hz), 4.63 (1H, m) 3.22 (1H,dd, J 13.8, 4.5 Hz) 3.00 (1H, m), 1.64-1.55 (9H, m) 1.35 (1H, m), 1.15(1H, m); m/z (ES⁺, 70V) 538.0 (MH⁺).

EXAMPLE 196 Ethyl(2S)-2-[(2-chloro-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared in a similar manner to the compound of Example 61 from thecompound of Example 5 (3.2 mmol) and N-chlorosuccinimide (3.5 mmol) togive the title compound as a white powder (0.9 mmol, 31%). δH (DMSO d⁶,300K) 9.05 (1H, d, J 9.0 Hz), 8.79 (2H, s) 7.60 (2H, d, J 8.5 Hz) 7.25(2H, d, J 8.5 Hz) 4.70 (1H, m) 4.19 (2H, q, J 7.1 Hz) 3.22 (1H, dd, J13.9, 5.0 Hz) 3.02 (1H, dd, J 13.9, 9.2 Hz) 1.21 (3H, q, J 7.1 Hz) 1.23(3H, s) 1.04 (3H, s); m/z (ES⁺, 70V) 512.0 (MH⁺).

EXAMPLE 197 1-Methyl-3-pyrrolidinyl(2S)-2-[(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{4-[(3.5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared in a similar manner to the compound of Example 138 from thecompound of Example 34 (0.65 mmol), EDC (0.72 mmol), HOBT (0.72 mmol)and 1-methyl-3-pyrrolidinol (1.95 mmol) in DMF (5 ml) to give the titlecompound (0.25 mmol, 40%) δH (CD₃OD) 8.55 (2H, s), 7.52 (2H, d, J 8.5Hz), 7.20 (2H, d, J 8.5 Hz), 4.92, (1H, m), 3.38 (1H, dd, obscured byMeOH) 2.96 (1H, dd, J 13.9, 9.2 Hz) 2.50-2.18 (4H, m) 2.18 (3H, s)1.89-1.56 (m, 4H), 1.12 (3H, s), 1.00 (3H, s), m/z (ES⁺, 70V) 625.0(MH⁺).

EXAMPLE 198 Isopropyl(2S)-2-(2-bromo-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared in a similar manner to the compound of Example 138 from thecompound of Example 34 (0.65 mmol), EDC (0.84 mmol), HOBT (0.84 mmol)and isopropanol (2.28 mmol) in DMF (5 ml) to give the title compound(0.25 mmol, 34%). δH (DMSO d⁶) 10.88 (1H, s) 9.69 (1H, d, J 9.0 Hz) 8.79(2H, s) 7.59 (2H, J 8.5 Hz) 7.28 (2H, d, J 8.5 Hz), 4.97 (1H, m) 4.75(1H, m) 3.20 (1H, dd, J 13.9, 5.1 Hz) 3.03 (1H, dd, J 14.0, 9.2 Hz) 1.24(m, 6H) 1.14 (3H, s) 1.05 (3H, s); m/z (ES⁺, 70V) 570.0 (MH⁺).

EXAMPLE 199 Ethyl(2S)-3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-(3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoate

The title compound was prepared in a similar manner to that of thecompound of Example 27 (coupling of amino acid ethyl ester (1.68 mmol),dione (1.68 mmol) in DCM (5 ml)) to give the title compound as a yellowpowder (1.1 mmol, 66%). δH (CD₃OD) 7.83 (2H, d, J 8.3 Hz), 7.55-7.35(4H, m), 7.47 (2H, d, J 8.4 Hz), 4.62 (1H, s), 4.50 (3H, m), 3.50 (1H,m), 3.08 (1H, m) 2.05-1.55 (11H, m) 1.49 (3H, t, J 7.1 Hz); m/z (ES⁺,70V) 501.0 (MH⁺).

EXAMPLE 200 Ethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4-(2,6-dichlorobenzoylamino)phenyl]propanoate

Prepared in a similar manner to the compound of Example 72 from thecompound of Example 199 (1.08 mmol) to give the title compound as yellowpowder (0.86 mmol, 80%). δH (CD₃OD) 7.53 (2H, d, J 8.4 Hz), 7.38-7.15(4H, m), 7.17 (2H, d, J 8.4 Hz), 5.32 (1H, m) 4.65 (1H, m), 3.22 (1H,dd, J 13.9, 4.4 Hz), 3.18 (q, 2H, J 7.1 Hz) 2.95 (1H, dd J 13.9, 9.5Hz,), 1.85-1.20 (14H, m); m/z (ES⁺, 70V) 581.0 (MH⁺).

EXAMPLE 201(2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4-(2,6-dichlorobenzoylamino)phenyl]propanoicacid

Prepared in a similar manner to the compound of Example 2 from thecompound of Example 200 (0.85 mmol) to give the title compound as whitepowder (0.60 mmol, 60%). δH (DMSO d⁶) 13.39 (1H, br s), 10.70 (1H, d, J6.1 Hz), 8.81(1H, d, J 9.2 Hz), 7.61 (3H, m), 7.56 (1H, m), 7.23 (2H, d,J 8.2 Hz), 3.18 (1H, dd, J 13.9, 4.4 Hz), 2.98(1H, dd J 13.8, 9.6 Hz),2.89-1.20 (11H, m); m/z (ES⁺, 70V) 567.0 (MH⁺).

EXAMPLE 202 Isopropyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4-(2,6-dichlorobenzoylamino)phenyl]propanoate

Prepared in a similar manner to the compound of Example 138 from thecompound of Example 201 (0.78 mmol) to give the title compound (0.49mmol, 63%). δH (DMSO d⁶) 10.71 (1H, s), 8.89(1H, d, J 9.0 Hz), 7.62-7.47(5H, m), 4.97, (1H, m), 3.17 (1H, dd, J 13.8, 4.8 Hz), 3.00 (1H, dd J13.8, 9.7 Hz), 1.79-1.50 (8H, m) 1.35 (1H, m) 1.24-1.11 (7H, m). m/z(ES⁺, 70V) 609.0 (MH⁺).

EXAMPLE 203 Ethyl(2S)-3-[4-(3-methyl-[2,7]naphthyridin-1-ylamino)phenyl]-2-(3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoate

Prepared in a similar manner to that of the compound of Example 3 togive the title compound as a yellow powder (1.5 mmol, 76%). δH (CDCl₃)9.56 (1H, s), 8.53 (1H, d, J 5.8 Hz), 7.78 (2H, d, J 8.4 Hz), 7.45 (1H,d, J 5.8 Hz), 7.08 (2H, d, J 8.5 Hz), 6.89 (1H, s), 5.77 (1H, m), 4.57(1H, s), 4.27 (2H, q, J 7.1 Hz), 3.10 (2H, m), 2.54 (3H, s), 1.84-1.23(14H, m); m/z (ES⁺, 70V) 485.2 (MH⁺).

EXAMPLE 204 Ethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4-(3-methyl-[2,7]naphthyridin-1-ylamino)phenyl]propanoate

Prepared in a similar manner to the compound of Example 31 from thecompound of Example 203 (0.62 mmol), bromine (0.81 mmol) andtriethylamine (0.81 mmol) in DCM (5 ml) to give the title compound asyellow powder (0.25 mmol, 40%). δH (CD₃OD) 9.44 (1H, s), 8.34 (1H, d, J5.8 Hz), 7.43 (1H, d, J 5.8 Hz), 7.09 (2H, d, J 8.5 Hz), 6.81 (1H, s),4.87 (1H, m), 4.89 (1H, m), 4.13 (2H, q, J 7.1 Hz), 3.22 (1H, m),(obscured mostly by MeOH), 2.92 (1H, dd, J 14.0, 9.7 Hz), 2.34 (3H, s),1.58-1.26 (10H, m), 1.18 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 564.2 (MH⁺).

EXAMPLE 205(2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4-(3-methyl-[2,7]naphthyridin-1-ylamino)phenyl]propanoicacid

Prepared in a similar manner to to the compound of Example 2 from thecompound of Example 204 (0.22 mmol) to give the title compound as yellowpowder (0.20 mmol, 90%). δH (DMSO d⁶) 9.76 (1H, s), 9.70 (1H, s), 8.87(1H, s, J 9.5 Hz), 8.56 (1H, d, J 5.6 Hz), 7.87 (2H, d, J 8.4 Hz), 7.56(1H, d, J 5.6 Hz), 7.20 (2H, d, J 8.4 Hz), 6.96 (1H, s), 4.73 (1H, m),3.22 (1H, dd, J 13.9, 4.0 Hz), 2.93 (1H, dd J 13.5, 10.1 Hz,), 2.42 (3H,s), 1.80-1.00 (11H, m); m/z (ES⁺, 70V) 535.0 (MH⁺).

EXAMPLE 206(2S)-3-[4-(3-Methyl-[2,7]naphthyridin-1-ylamino)phenyl]-2-(3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoicacid

Prepared in a similar manner to the compound of Example 2 from thecompound of Example 203 (0.62 mmol) to give the title compound as whitepowder (0.27 mmol, 43%). δH (DMSO d⁶) 9.81 (1H, s), 9.52 (1H, s), 8.58(1H, d, J 5.6 Hz), 8.30 (1H, J 8.6 Hz), 7.86 (2H, d, J 8.4 Hz), 7.57(1H,d, J 5.6 Hz), 7.22 (2H, d, J 8.5 Hz), 6.97(1H, s), 4.08 (1H, m), 4.32(1H, s), 3.15 (1H, dd, J 13.7, 4.7 Hz), 2.97 (1H, dd, J 13.7, 9.5 Hz),2.44 (3H, s), 1.74-1.45 (9H, m), 1.24-1.15 (2H, m); m/z (ES⁺, 70V) 457.1(MH⁺).

EXAMPLE 207 Ethyl(2S)-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]-2-(3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoate

Prepared in a similar manner to the compound of Example 3 to give thetitle compound as a yellow powder (1.4 mmol, 73%) δH (CDCl₃) 9.61 (1H,s), 8.65 (1H, d, J 5.7 Hz), 8.25 (1H, d, J 5.8 Hz), 7.71 (2H, d, J 8.4Hz), 7.63 (1H, d, J 8.5 Hz), 7.12 (2H, d, J 8.5 Hz), 7.05 (1H, d, J 5.8Hz), 5.80 (1H, m), 4.55 (1H, s), 4.29 (2H, q, J 7.2 Hz), 3.13 (2H, m),1.87-1.25 (14H, m); m/z (ES⁺, 70V) 471.1 (MH⁺).

EXAMPLE 208 Ethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoate

Prepared in a similar manner to that of Example 31 from the compound ofExample 207 (0.64 mmol) to give the title compound as a yellow powder(0.45 mmol, 76%). δH (CDCl₃) 9.81 (1H, s), 8.64 (H, d, J 5.7 Hz), 8.29(1H, d, J 5.8 Hz), 7.75 (2H, d, J 8.3 Hz), 7.60 (1H, d, J 5.8 Hz), 7.12(2H, d, J 8.4 Hz), 7.08 (1H, d, J 5.7 Hz), 5.91 (1H, m), 5.03 (1H, m),4.28 (2H, q J 7.1 Hz), 3.29 (2H, m), 1.81-1.39 (10H, m), 1.35 (3H, t, J7.1 Hz); m/z (ES⁺, 70V) 550.0 (MH⁺).

EXAMPLE 209(2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propionicacid

Prepared in a similar manner to the compound of Example 2 from thecompound of Example 208 (0.40 mmol) to give the title compound as whitepowder (0.25 mmol, 64%) δH (DMSO d⁶, 300 K) 9.90 (1H, s), 9.56 (1H, s),8.86 (1H, d, J 9.3 Hz), 8.66 (1H, d, J 5.6 Hz), 8.17 (1H, d, J 5.7 Hz),7.81 (2H, d, J 8.2 Hz), 7.70 (1H, d, J 5.6 Hz), 7.24 (2H, d, J 8.4 Hz),7.14 (1H, d, J 5.7 Hz), 4.78 (1H, m) 3.23 (1H, dd, J 13.9 4.1 Hz), 2.99(1H, dd, J 13.7, 10.0 Hz), 1.81-1.04 (11H, m); m/z (ES⁺, 70V) 522.0(MH⁺).

EXAMPLE 210(2S)-3-[4-([2,7]Naphthyridin-1-ylamino)phenyl]-2-(3oxo-spiro[3.5]non-1-en-1-ylamino)propanoicacid

Prepared in a similar manner to the compound of Example 2 from thecompound of Example 207 (0.64 mmol) to give the title compound as whitepowder (0.211 mmol, 33%). δH (DMSO d⁶, 300K) 9.85 (1H, s), 9.54 (1H, s),8.67 (1H, d, J 5.6 Hz), 8.28 (1H, d, J 8.6 Hz), 8.18 (1H, d, J 5.6 Hz),7.78 (2H, d, J 8.3 Hz), 7.70 (1H, d, J 5.6 Hz), 7.23 (2H, d, J 8.4 Hz),7.14 (1H, d, J 5.7 Hz), 4.34 (1H, s), 4.08 (1H, m), 3.15 (1H, dd, J13.8, 4.8 Hz), 2.95 (1H, dd, J 13.8, 9.4 Hz), 1.74-1.39 (9H, m), 1.20(2H, m); m/z (ES⁺, 70V) 443.1 (MH⁺).

EXAMPLE 211(2S)-3-[4-([2,7]Naphthyridin-1-yloxy)phenyl]-2-(3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoicacid

Prepared in a similar manner to the compound of Example 2 from thecompound of Example 35 (0.70 mmol) to give the title compound as a whitepowder (0.56 mmol, 80%). δH (DMSO d⁶, 300K) 9.70 (1H, s), 8.81 (1H, d, J5.7 Hz), 8.30 (1H, d, J 8.8 Hz), 8.10 (1H, d J 5.8 Hz), 7.89 (1H, d, J5.7 Hz), 7.53 (1H, d, J 5.9 Hz), 7.34 (1H, d, J 8.5 Hz), 7.23 (2H, d, J8.5 Hz), 4.34 (1H, s), 4.15 (1H, m), 3.21 (1H, dd, J 14.0, 4.8 Hz), 3.00(1H, dd, J 13.8, 9.7 Hz), 1.71-1.50 (11H, m); m/z (ES⁺, 70V) 444.6(MH⁺).

EXAMPLE 212 Ethyl(2S)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}-2-(2-hydroxy-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoate

To a solution of the compound of Example 27 (1.0 g, 1.9 mmol) in DCM (40ml) at −40° C. was added lead tetraacetate (0.94 g, 1.1 eq). The mixturewas allowed to warm to 0° C. and stirred at this temperature for 8 h.The reaction mixture was partitioned between EtOAc (200 ml) and water(100 ml), the organics were separated washed with water (2×100 ml),brine (50 ml), dried (MgSO₄), filtered and concentrated in vacuo to givea crude oil. The crude was dissolved in ethanol (10 ml) and treated withNaH (100 mg). The mixture was stirred at room temperature until TLCanalysis indicated that all starting material had been consumed. Thereaction was quenched by the addition of NH₄Cl (5 ml, sat. aq.), EtOAc(2×20 ml) extraction of the mixture followed by washing with water (10ml), brine (10 ml), drying (MgSO₄), filtering and concentration in vacuoto give a crude product which was purified by column chromatography(SiO₂, EtOAc:Hexane 1:1) to give the title compound as a white foam(0.89 g, 86%). δH (DMSO d⁶, 400 MHz) 10.83 (1H, br), 8.78 (2H, s), 7.51(2H, d, J 8.5 Hz), 7.12 (2H, d, J 8.5 Hz), 4.94 (1H, dd, J 11.4, 5.0Hz), 4.10 (2H, m), 3.33 (1H, dd, J 14.1, 4.9 Hz), 3.14 (1H, dd, J 14.0,11.4 Hz), 1.40-1.63 (4H, m), 1.19-1.33 (6H, m), 1.16 (3H, t, J 7.1 Hz);m/z (ES⁺, 70V) 532 (MH⁺).

EXAMPLE 213 Ethyl(2S)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}-2-(2-methoxy-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoate

To a solution of the compound of Example 212 (0.8 g, 1.5 mmol) inacetone (15 ml) was added K₂CO₃ (5 g) and methyl iodide (2.5 ml). Themixture was stirred at room temperature for 5 days. The mixture wasfiltered and concentrated in vacuo and the residue purified by columnchromatography (SiO₂, EtOAc:Hexane 1:1) to give the title compound as awhite solid (0.45 g, 55%). δH (DMSO d⁶, 400 MHz) 8.50 (2H, d, J 4.8 Hz),7.21 (2H, d, J 8.4 Hz), 7.04 (2H, d, J 8.4 Hz), 4.87 (1H, dd, J 11.8,4.9 Hz), 4.00-4.16 (2H, m), 3.34 (3H, s), 3.26 (1H, dd, J 13.9, 4.9 Hz),3.07 (1H, dd, J 13.9, 11.6 Hz), 1.15-1.66 (10H, m), 1.12 (3H, t, J 7.0Hz); m/z (ES⁺, 70V) 546 (MH⁺).

EXAMPLE 214 Ethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-(2,4,6-trimethoxyry[1,1′-biphenyl]-4-yl)propanoate

The title compound was prepared by the methods as described herein. δH(CDCl₃) 7.19 (2H, d, J 8.1 Hz), 7.04 (2H, d, J 8.1 Hz), 6.14 (2H, s),5.84 (1H, d, J 8.6 Hz), 4.98 (1H, m), 4.20 (2H, q, J 7.1 Hz), 3.78 (3H,s), 3.62 (6H, s), 3.21 (2H, d), 1.97-1.40 (10H, m), 1.24 (3H, t, J 7.1Hz); m/z (ES⁺, 70V) 572 (MH⁺).

EXAMPLE 215(2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-(2,4,6-trimethoxy[1,1′-biphenyl]-4-yl)propanoicacid

Prepared from the compound of Example 214 by the method of Example 2 togive the title compound. δH (DMSO d⁶) 12.30 (1H, br s), 8.79 (2H, d, J10.0 Hz), 7.19 (2H, d, J 8.1 Hz), 7.08 (2H, d, J 8.1 Hz), 6.29 (2H, s),4.78 (1H, m), 3.81 (3H, s), 3.61 (6H, s), 3.27 (1H, m), 2.98 (1H, dd, J13.4, 10.2 Hz), 1.95-1.00 (10H, m); m/z (ES⁺, 70V) 544 (MH⁺).

EXAMPLE 216 Tetrahydro-furan-2-ylmethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate

Prepared using a similar procedure to that for the preparation of thecompound of Example 138 from the compound of Example 32 (0.25 g, 0.44mmol), EDC (150 mg), HOBT (100 mg) and tetrahydrofurfurylalcohol (0.5ml) in DMF (2 ml) to give the title compound (0.15 g, 52%). δH (400 MHz,DMSO d⁶) 10.88 (1H, s), 8.93 (1H, d, J 9.1 Hz), 8.80 (2H, s), 7.60 (2H,d, J 8.3 Hz), 7.28 (2H, d, J 6.9 Hz), 4.84 (1H, m), 4.15 (2H, m), 4.05(1H, m), 3.23 (1H, dd, J 13.8, 4.4 Hz), 3.04 (1H, dd, J 13.6, 9.6 Hz),1.50-2.00 (14H, m); m/z (ES⁺, 70V) 650 (MH⁺).

The following assays can be used to demonstrate the potency andselectivity of the compounds according to the invention. In each ofthese assays an IC₅₀ value was determined for each test compound andrepresents the concentration of compound necessary to achieve 50%inhibition of cell adhesion where 100%=adhesion assessed in the absenceof the test compound and 0%=absorbance in wells that did not receivecells.

α₄β₁ Integrin-Dependent Jurkat Cell Adhesion to VCAM-Ig

96 well NUNC plates were coated with F(ab)₂ fragment goat anti-human IgGFcγ-specific antibody [Jackson Immuno Research 109-006-098:100 μl at 2μg/ml in 0.1M NaHCO₃, pH 8.4], overnight at 4°. The plates were washed(3×) in phosphate-buffered saline (PBS) and then blocked for 1 h inPBS/1% BSA at room temperature on a rocking platform. After washing (3×in PBS) 9 ng/ml of purified 2d VCAM-Ig diluted in PBS/1% BSA was addedand the plates left for 60 minutes at room temperature on a rockingplatform. The plates were washed (3× in PBS) and the assay thenperformed at 37° for 30 min in a total volume of 200 μl containing2.5×10⁵ Jurkat cells in the presence or absence of titrated testcompounds.

Each plate was washed (2×) with medium and the adherent cells were fixedwith 100 μl methanol for 10 minutes followed by another wash. 100 μl0.25% Rose Bengal (Sigma R4507) in PBS was added for 5 minutes at roomtemperature and the plates washed (3×) in PBS. 100 μl 50% (v/v) ethanolin PBS was added and the plates left for 60 min after which theabsorbance (570 nm) was measured.

α₄β₇ Integrin-Dependent JY Cell Adhesion to MAdCAM-Ig

This assay was performed in the same manner as the α₄β₁ assay exceptthat MAdCAM-Ig (150 ng/ml) was used in place of 2d VCAM-Ig and asub-line of the β-lympho blastoid cell-line JY was used in place ofJurkat cells. The IC₅₀ value for each test compound was determined asdescribed in the α₄β₁ integrin assay.

α₅β₁ Integrin-Dependent K562 Cell Adhesion to Fibronectin

96 well tissue culture plates were coated with human plasma fibronectin(Sigma F0895) at 5 μg/ml in phosphate-buffered saline (PBS) for 2 hr at37° C. The plates were washed (3× in PBS) and then blocked for 1 h in100 μl PBS/1% BSA at room temperature on a rocking platform. The blockedplates were washed (3× in PBS) and the assay then performed at 37° C. ina total volume of 200 μl containing 2.5×105 K562 cells,phorbol-12-myristate-13-acetate at 10 ng/ml, and in the presence orabsence of titrated test compounds. Incubation time was 30 minutes. Eachplate was fixed and stained as described in the α₄β₁ assay above.

α_(m)β₂-Dependent Human Polymorphonuclear Neutrophils Adhesion toPlastic

96 well tissue culture plates were coated with RPMI 1640/10% FCS for 2 hat 37° C. 2×10⁵ freshly isolated human venous polymorphonuclearneutrophils (PMN) were added to the wells in a total volume of 200 μl inthe presence of 10 ng/ml phorbol-12-myristate-13-acetate, and in thepresence or absence of test compounds, and incubated for 20 min at 37°C. followed by 30 min at room temperature. The plates were washed inmedium and 100 μl 0.1% (w/v) HMB (hexadecyl trimethyl ammonium bromide,Sigma H5882) in 0.05M potassium phosphate buffer, pH 6.0 added to eachwell. The plates were then left on a rocker at room temperature for 60min. Endogenous peroxidase activity was then assessed using tetramethylbenzidine (TMB) as follows: PMN lysate samples mixed with 0.22% H₂O₂(Sigma) and 50 μg/ml TMB (Boehringer Mannheim) in 0.1M sodiumacetate/citrate buffer, pH 6.0 and absorbance measured at 630 nm.

αIIb/β₃-Dependent Human Platelet Aggregation

Human platelet aggregation was assessed using impedance aggregation onthe Chronolog Whole Blood Lumiaggregometer. Human platelet-rich plasma(PRP) was obtained by spinning fresh human venous blood anticoagulatedwith 0.38% (v/v) tri-sodium citrate at 220×g for 10 min and diluted to acell density of 6×10⁸/ml in autologous plasma. Cuvettes contained equalvolumes of PRP and filtered Tyrode's buffer (g/liter: NaCl 8.0;MgCl₂.H₂O 0.427; CaCl₂ 0.2; KCl 0.2; D-glucose 1.0; NaHCO₃ 1.0;NaHPO₄.2H₂O 0.065). Aggregation was monitored following addition of 2.5μM ADP (Sigma) in the presence or absence of inhibitors.

In the above assays the preferred compounds of the invention such as thecompounds of the Examples generally have IC₅₀ values in the α₄β₁ andassay of 1 μM and below and in the α₄β₇ assay of 5 μM and below. In theother assays featuring α integrins of other subgroups the same compoundshad IC₅₀ values of 50 μM and above thus demonstrating the potency andselectivity of their action against α₄ integrins.

The invention is illustrated by the foregoing intermediates andexamples, which are not intended to be limiting. Those skilled in theart will appreciate that numerous changes and modifications may be madeto the preferred embodiments of the invention and that such changes andmodifications may be made without departing from the spirit of theinvention. It is therefore intended that the appended claims cover allsuch equivalent variations as fall within the true spirit and scope ofthe invention.

1. A compound of formula (1):

wherein R¹ is a group Ar¹L²Ar²Alk in which: Ar¹ is an optionallysubstituted aromatic or heteroaromatic group; L² is a covalent bond or alinker atom or group; Ar² is an optionally substituted arylene orheteroarylene group; and Alk is a chain

in which R is a carboxylic acid (—CO₂H) or a derivative or biosterethereof; X is an —O— or —S— atom or —N(R²)— group in which: R² is ahydrogen atom or a C₁₋₆alkyl group; V is an oxygen (O) or sulphur (S)atom; R^(x), R^(y) and R^(z) which may be the same or different is eachan atom or group -L¹(Alk¹)_(n)(R³)_(v) in which L¹ is a covalent bond ora linker atom or group, Alk¹ is an optionally substituted aliphatic orheteroaliphatic chain, R³ is a hydrogen or halogen atom or groupselected from —OR^(3a) [where R^(3a) is a hydrogen atom or an optionallysubstituted straight or branched C₁₋₆alkyl group or C₃₋₈cycloalkylgroup], SR^(3a), —CN or an optionally substituted cycloaliphatic,heterocycloaliphatic, polycycloaliphatic, heteropolycycloaliphatic,aromatic or heteroaromatic group, n is zero or the integer 1 and v isthe integer 1, 2 or 3 provided that when n is zero and L¹ is a covalentbond v is the integer 1; or R^(z) is an atom or group as previouslydefined and R^(x) and R^(y) are joined together to form an optionallysubstituted spiro linked cycloaliphatic or heterocycloaliphatic group;and the salts, solvates, hydrates and N-oxides thereof.
 2. A compoundaccording to claim 1 in which Alk is a —CH₂CH(R)— or —CH(CH₂R)— chain.3. A compound according to claim 1 in which R is a carboxylic acid(—CO₂H) group.
 4. A compound according to claim 1 in which R is anesterified carboxyl group of formula —CO₂Alk⁷.
 5. A compound accordingto claim 1 in which X is an —N(R²)— group.
 6. A compound according toclaim 5 in which R² is a hydrogen atom.
 7. A compound according to claim1 in which Ar² is an optionally substituted phenylene group or anoptionally substituted pyridinediyl group of formula:

where a and b signify the points of attachment of L² and Alkrespectively.
 8. A compound according to claim 1 in which Ar¹ is anoptionally substituted phenyl or five-, six- or ten-memberedheteroaromatic group.
 9. A compound according to claim 8 in which Ar¹ isan optionally substituted pyridyl, pyrimidinyl, naphthyridinyl,quinolinyl or isoquinolinyl group.
 10. A compound according to claim 1in which R^(z) is a halogen atom.
 11. A compound according to claim 1 inwhich R^(z) is an optionally substituted C₁₋₈alkyl group.
 12. A compoundaccording to claim 1 in which R^(z) is a group —L¹(Alk¹)_(n)R³ in whichL¹ is an —O—, —S— or —Se— atom or —S(O)— or —N(R⁸)— group.
 13. Acompound according to claim 12 in which n is zero.
 14. A compoundaccording to claim 12 in which n is the integer 1 and Alk¹ is anoptionally substituted C₁₋₆alkylene chain.
 15. A compound according toclaim 12 in which R³ is a hydrogen atom or an optionally substitutedC₃₋₁₀cycloaliphatic, C₃₋₁₀heterocycloaliphatic, C₆₋₁₂aromatic or C₁₋₉heteroaromatic group.
 16. A compound according to claim 1 in which R^(z)is a group —L¹(Alk¹)_(n)R³ in which L¹ is a covalent bond.
 17. Acompound according to claim 16 in which n is zero.
 18. A compoundaccording to claim 16 in which n is the integer 1 and Alk¹ is anoptionally substituted C₁₋₆alkylene chain.
 19. A compound according toclaim 16 in which R³ is a hydrogen atom or an optionally substitutedC₃₋₁₀cycloaliphatic, C₃₋₁₀heterocycloaliphatic, C₆₋₁₂aromatic orC₁₋₉heteroaromatic group.
 20. A compound according to claim 1 in whichR^(x) and R^(y) is each an optionally substituted C₁₋₈alkyl group.
 21. Acompound according to claim 1 in which R^(x) and R^(y) are joined toform an optionally substituted spiro linked C₃₋₁₀ cycloaliphatic orC₃₋₁₀heterocycloaliphatic group.
 22. A compound which is:(2S)-2-[(3-Oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(3-Oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoicacid(2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(2,7)naphthyridin-1-yloxy]phenyl}propanoicacid(2S)-2-[(2-Bromo-3-oxo-7-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-{(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino}-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoicacid(2S)-2-[(3-Oxospiro[3.6]dec-1-en-1-yl)amino]3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-3-oxospiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-{[4,4-Dimethyl-2-(phenylselenenyl)-3-oxo-1-cyclobutenyl]amino}-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-7-methoxy-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-{(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino}-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoicacid(2S)-2-{[2-(Phenylsulfanyl)-4,4-dimethyl-3-oxo-1-cyclobutenyl]amino}-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Chloro-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-pyridin-3-yl-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-2-[(2-iodo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoicacid(2S)-2-[(2-Chloro-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoicacid(2S)-2-[(2-Chloro-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Chloro-3-oxo-spiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[4,4-Dimethyl-2-(1-methyl-1H-tetrazol-5-ylsulfanyl)-3-oxo-cyclobut-1-enylamino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-3,7,7-trioxo-7λ⁶-thia-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Chloro-3-oxo-spiro[3.4-]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloro-isonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-3-oxo-spiro[3.4-]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Methylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-(2-Fluoro-3-oxo-spiro[3.5]non-1-en-1-ylamino)3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Fluoro-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(4,4-Dimethyl-2-methylsulfanyl-3-oxo-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Isopropylsulfanyl-4,4-dimethyl-3-oxo-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Isopropylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Isopropylsulfanyl-4,4-dimethyl-3-oxo-cyclobut-1-enyl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoicacid(2S)-2-[(2-Isopropylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoicacid(2S)-2-[(2-Isopropylsulfanyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoicacid(2S)-2-[(2-Bromo-3-oxo-spiro[3.4-]octa-1,6-dien-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(4,4-Dimethyl-3-oxo-2-pentafluorophenylsulfanyl-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(4,4-Dimethyl-3-oxo-2-pyrazin-2-yl-cyclobut-1-enyl)amino]-3-{4[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(7-Acetyl-2-bromo-3-oxo-7-aza-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-{[2-(Isopropylsulfanyl)-3-oxo-7-oxaspiro[3.5]non-1-en-yl)]amino}-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoicacid(2S)-2-[(2-Cyclohexyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-methyl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-propyl-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-methyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-propyl-7-oxa-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-[1,3]dithian-2-yl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-ethyl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-3-{4-[(3,5-Dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}-2-(3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoicacid(2S)-2-(2-Chloro-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoicacid(2S)-3-{4-[(3,5-Dichloro-1-oxy-pyridine-4-carbonyl)-amino]-phenyl}-2-(2-methanesulfinyl-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)propanoic acid(2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4-(3-methyl-[2,7]naphthyridin-1-ylamino)phenyl]propanoicacid(2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoicacid(2S)-2-(2-Bromo-4,4-dimethyl-3-oxo-cyclobut-1-enylamino)-3-[4-(3-methyl-[2,7]naphthyridin-1-yloxy)phenyl]propanoicacid(2S)-2-[(2-Bromo-3-oxo-spiro[3.4-]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid and the salts, solvates, hydrates, N-oxides and carboxylic acidesters thereof.
 23. A compound which is:(2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-3-oxo-7-oxaspiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-3-oxospiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-{(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino}-3-{4-[(3-methyl[2,7]naphthyridin-1-yl)oxy]phenyl}propanoicacid(2S)-2-{[2-(Phenylsulfanyl)-4,4-dimethyl-3-oxo-1-cyclobutenyl]-amino}-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Chloro-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-pyridin-3-yl-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-2-[(2-Iodo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoicacid(2S)-2-[(2-Chloro-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{5-[(3,5-dichloroisonicotinoyl)amino]pyridin-2-yl}propanoicacid(2S)-2-[(2-Chloro-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Chloro-3-oxo-spiro[3.6]dec-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-3,7,7-trioxo-7λ⁶-thia-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Chloro-3-oxo-spiro[3.4-]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Bromo-3-oxo-spiro[3.4-]oct-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Methylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-(2-Fluoro-3-oxo-spiro[3.5]non-1-en-1-ylamino)3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Fluoro-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(4,4-Dimethyl-2-methylsulfanyl-3-oxo-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Isopropylsulfanyl-4,4-dimethyl-3-oxo-cyclobut-1-enyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Isopropylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Isopropylsulfanyl-4,4-dimethyl-3-oxo-cyclobut-1-enyl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoicacid(2S)-2-[(2-Isopropylsulfanyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoicacid(2S)-2-[(2-Isopropylsulfanyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1-yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoicacid(2S)-2-[(2-Bromo-3-oxo-spiro[3.4-]octa-1,6-dien-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(7-Acetyl-2-bromo-3-oxo-7-aza-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)-2-[(2-Cyclohexyl-3-oxo-spiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoicacid(2S)3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-methyl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(3-oxo-2-propyl-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-2-(2-[1,3]dithian-2-yl-3-oxo-spiro[3.5]non-1-en-1-ylamino)propanoicacid(2S)-2-(2-Bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoicacid2-(2-Chloro-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloro-1-oxy-pyridine-4-carbonyl)amino]phenyl}propanoicacid and the salts, solvates, hydrates, N-oxides and carboxylic acidesters thereof.
 24. A compound which is: Ethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoateIsopropyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoatet-Butyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate1-Methyl-piperidin-4-yl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoatePhenyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoateCyclopentyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate2-Imidazol-1-yl-ethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoateNeopentyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoateTetrahydro-furan-3-yl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoatePyridin-4-ylmethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoateTetrahydropyran-4-yl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]-phenyl}propanoate1-Methyl-pyrrolidin-3-yl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate2,3-Dihydroxypropyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoateTetrahydrofuran-2-ylmethyl(2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoateand the salts, solvates, hydrates and N-oxides thereof.
 25. Apharmaceutical composition comprising a compound according to claim 1together with one or more pharmaceutically acceptable carriers,excipients or diluents.
 26. A method for the prophylaxis or treatment ofa disease or disorder in a mammal in which the extravasation ofleukocytes plays a role, comprising administering to a mammal sufferingfrom such a disease or disorder a therapeutically effective amount of acompound according to claim
 1. 27. A method according to claim 26wherein said disease or disorder is selected from the group consistingof inflammatory arthritis, multiple sclerosis, allograft rejection,diabetes, inflammatory dermatoses, asthma and inflammatory boweldisease.
 28. A method according to claim 27 wherein said inflammatoryarthritis is selected from the group consisting of rheumatoid arthritisvasculitis and polydermatomyositis.
 29. A method according to claim 27wherein said inflammatory dermatoses are selected from the groupconsisiting of psoriasis and dermatitis.
 30. A method for inhibiting, ina mammal, the binding of a4 integrins to the ligands thereof, comprisingadministering to the mammal an effective amount of a compound accordingto claim
 1. 31. A method according to claim 30 wherein said α4 integrinsare selected from the group consisiting of α4β1 and α4β7 integrins.